Sepsis roadmap: What we know, what we learned, and where we are going

Journal Pre-proof Sepsis roadmap: What we know, what we learned, and where we are going

Kumar Vijay PII:

S1521-6616(18)30548-5

DOI:

https://doi.org/10.1016/j.clim.2019.108264

Reference:

YCLIM 108264

To appear in:

Clinical Immunology

Received date:

5 September 2018

Revised date:

2 July 2019

Accepted date:

26 September 2019

Please cite this article as: K. Vijay, Sepsis roadmap: What we know, what we learned, and where we are going, Clinical Immunology(2018), https://doi.org/10.1016/ j.clim.2019.108264

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© 2018 Published by Elsevier.

Journal Pre-proof Sepsis roadmap: What we know, what we learned, and where we are going Kumar Vijay1,2,* [email protected], [email protected] 1

Children’s Health Queensland Clinical Unit, School of Clinical Medicine, Faculty of Medicine, Mater Research, University of Queensland, ST Lucia, Brisbane, Queensland 4078, Australia 2

School of Biomedical Sciences, Faculty of Medicine, University of Queensland, ST Lucia, Brisbane, Queensland 4078, Australia *

Corresponding author at: Children’s Health Clinical Unit, Faculty of Medicine, Mater Research, University of Queensland, ST Lucia, Brisbane, Queensland 4078, Australia. Abstract

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Sepsis is a life-threatening condition originating as a result of systemic blood infection causing, one or more organ damage due to the dysregulation of the immune response. In 2017, the world health organization (WHO) declared sepsis as a disease of global health

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priority, needing special attention due to its high prevalence and mortality around the world.

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Most of the therapeutics targeting sepsis have failed in the clinics. The present review highlights the history of the sepsis, its immunopathogenesis, and lessons learned after the

describes

in

details

the

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failure of previously used immune-based therapies. The subsequent section, where to go importance

of the

complement

system (CS),

autophagy,

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inflammasomes, and microbiota along with their targeting to manage sepsis. These systems are interconnected to each other, thus targeting one may affect the other. We are in an urgent

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need for a multi-targeting therapeutic approach for sepsis.

system 1. Introduction

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Key Words: Sepsis; immune system; autophagy; microbiota; inflammasomes; complement

Sepsis is known to ancient Greeks since the time of Hippocrates (460-370 BC) as a condition causing the putrefaction of the body without its microbial association. Later on, the Persian philosopher and physician Ibna Sina or Avicenna (AD 980–1037) first described the sepsis/septicemia as putrefaction of blood and tissues with fever [1]. Since then many scientists contributed to the sepsis research. For example, Anton van Leeuwenhoek (16321723, Father of Microbiology) first described microbes by discovering and modifying the compound microscope. Edward Jenner (17th May 1749 – 26th January 1823) introduced the smallpox vaccine and was considered as the Father of Immunology. Louis Pasture (27 th December 1822 – 28th September 1895), a French microbiologist introduced the concept of microbial

fermentation

and

pasteurization,

a

sterilization

technique.

However,

Ignaz

Semmelweis (a Vienna, Austria-based obstetrician, 1818-1865) initially gave the classic 1

Journal Pre-proof concept of sepsis during his study on puerperal fever (also called childbed fever) in infants. He first described that the decomposed animal matter entering into the blood of children is the actual cause of the childbed fever. Thus, a new era started to understand the sepsis and its pathogenesis. Hugo Schottmüller (1914) for the first time established the presence of infection is essential for sepsis pathogenesis [1, 2]. In 1989, Roger C. Bone (1941-1997), a Chicago (USA)-based pulmonary and critical care specialist defined sepsis as a disease of microbial invasion (including their products/toxins) to the peripheral circulation profoundly activating the immune system to cause systemic inflammatory response syndrome (SIRS) [3, 4]. This

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definition of the sepsis remained valid till sepsis-3 or the third consensus of sepsis held in 2016. Sepsis-3 defines it as a life-threatening condition associated with organ dysfunction as a result of the impaired immune response during systemic infection [5]. Sepsis-3 also

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developed qSOFA (quick Sequential Organ Failure Assessment) scoring system for the early

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identification of simultaneous organ dysfunction and challenged the SIRS criteria [6-9]. Sepsis-3 guidelines have omitted the SIRS criteria [10, 11]. The SIRS criteria do not

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determine the immune dysregulation-associated threat to the life of the patient with sepsis [10, 12, 13]. Hence, sepsis 3 emphasizes the early diagnosis and quick initiation of the

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therapy required to treat sepsis in preventing the associated mortality. In 2017, the World Health Assembly (WHA) and WHO declared sepsis as a global health priority [14]. However,

persisting

even

with

volume

resuscitation

requiring

the

treatment

with

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hypotension

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sepsis-3 guidelines have overlooked the use of severe sepsis [15]. Sepsis with the

vasopressors is called septic shock [7, 16, 17]. Thus sepsis has traveled a very long journey since the time of Hippocrates. During this journey, lots of novel breakthroughs have been achieved to manage sepsis that includes immunomodulatory molecules, which failed in clinics. Despite the failure, the sepsis research and refined clinical practices have increased in the past 30 years [18]. The major aim of the article is to highlight the current understanding of the sepsis pathogenesis, lessons learned, and the future therapeutic/early diagnostic approaches to target sepsis. 2. Lessons Learned The initial encounter of the pathogen with the host at the entry sites including respiratory tract (Lungs), gastrointestinal tract (gut), or skin may induce sepsis depending on the immune status of the host (Fig.1) [19, 20]. For example, sepsis proves lethal in females as compared to males of the same age [21-23]. This may be explained as consequence of the gender-based differences in the immune function [24]. Mast cells (MCs)-mediated release of 2

Journal Pre-proof prestored cytokines (TNF-α and IL-6) plays a crucial role in the clearance of bacterial pathogens. The release of prestored pro-inflammatory cytokines from MCs induces the migration of neutrophils and monocytes at the site of infection including bacterial peritonitis [25, 26]. However, the activation of mast cells also decreases the phagocytic potential of peritoneal macrophages by releasing the prestored IL-4, and the inhibition of this cytokine prevents this immune defect [27]. Thus MCs act as two edge sword in the pathogenesis of sepsis by secreting TNF-α and IL-6 they send signals for local neutrophil and monocyte infiltration. On the other hand, by secreting IL-4 in a TLR4-dependent manner, within the first fifteen minutes of bacterial peritonitis, they suppress the phagocytic potential of the

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peritoneal macrophages and increase the bacterial load that may induce bacteremia and sepsis. Thus it will be interesting to study these cells extensively during skin infectionassociated sepsis because MCs are sentinel cells governing both innate and adaptive

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immunity [28].

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The pro-inflammatory action of MCs depends on the sex of the organism [29]. The primary bone marrow-derived mast cells (BMMCs) isolated from female mice exhibit higher pro-

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inflammatory action due to the release of the increased amount of β-hexosaminidase, histamine, tryptase, and TNF-α as compared to BMMCs isolated from male mice [29]. Thus

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MCs isolated from female mice store a higher amount of prestored pro-inflammatory mediators as compared to their male counterparts. Additionally, female mice exhibit an

the

circulation,

and

increased

intestinal permeability

during

passive

systemic

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into

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increased MC-dependent immune response (hyperthermia, increased secretion of histamine

anaphylaxis (PSA) challenge). The increased secretion of pro-inflammatory mediators by female MCs depends on their high capacity to synthesize and store MC-granule mediators [29]. Another study has shown the increased release of pro-inflammatory mediators from freshly isolated peritoneal MCs from female mice as compared to the age-matched males [30]. Among age-matched adults, human females are more prone to develop asthma as compared to their counterpart males due to higher estradiol and progesterone levels directly affecting MC-based immune function responsible for asthma [31]. Thus an increased proinflammatory action of MCs in females may protect them from severe infections. But this uncontrolled pro-inflammatory condition may lead to the development of sepsis-like conditions. Hence it becomes crucial to choose the sex of the animals used for sepsis research to

design future immunomodulation approaches. Most sepsis-based studies

published in high-quality journals do not identify the sex of the animals used [32]. Even cell culture-based studies do not identify the age and sex of the animals from which the primary 3

Journal Pre-proof immune cells isolated [32]. Hence the identification of the sex of the animal becomes a crucial factor for the immune-based sepsis research due to its impact on the immunological parameters studied. Macrophages and neutrophils also serve as the first line of defense against pathogens causing sepsis [33, 34]. The initial activation of these innate immune cells in a controlled manner prevents the development of sepsis through mounting an effective immune response required to clear the pathogen. However, the failure of these cells in containing the infection frustrates them that induces the development of cytokine storm [Secretion of a large amount of both pro-inflammatory (TNF-α, IL-1, IL-6, IL-8, IL-12, and IFN-γ) and anti-inflammatory

dysregulates

the

immune

response

responsible

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cytokines (IL-1ra, IL-4, IL-10, and TGF-β1)] [35-39]. The cytokine storm profoundly for

the

induction

of disseminated

intravascular coagulation (DISC), multi-organ dysfunction syndrome (MODS), and death of

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the patient (Fig. 1) [38]. The role of pro-inflammatory cytokines in sepsis pathogenesis was

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determined earlier and led to the development of TNF-α, IL-1, IL-12, IL-6, and macrophage migration factor (MIF) targeting via designing monoclonal antibodies. However, all these

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antibody-based targetings of specific pro-inflammatory cytokines failed in clinical trials [4042].

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The subsequent discovery of the TLR4 as a pattern recognition receptor (PRR) in 1997 proved to be a milestone for host-pathogen interaction researchers [43]. The involvement of

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TLR4 in the host-pathogen interaction led to the development of Eritoran (E5564, a TLR4

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antagonist). However, Eritoran worked well in animal models but failed in sepsis clinical trial [44, 45]. This failure did not stop the TLR-based sepsis research, and further studies indicated that plasma levels of soluble TLR2 (sTLR2) serve as a better biomarker for sepsis than C-reactive protein (CRP) [46, 47]. Additionally, the plasma sTLR2 level serves as a better biomarker in discriminating between sepsis and SIRS originating in the absence of infection [46]. Thus sTLR2 may serve as a novel biomarker for sepsis as well making a clear difference between sepsis and non-infectious SIRS by the attending ICU specialists. In addition to sTLR2, sTLR4 also serves as a potential biomarker for sepsis [47]. Thus, no matters TLR4 antagonists failed in the clinic to manage the sepsis, but they still have a bright future in sepsis research. Recombinant activated protein C (rAPC) or Drotrecogin alfa (activated) (DrotAA) developed by Eli Lily Co. USA and approved by USFDA in 2001 for the management of sepsis-associated DISC and septic shock also failed in clinical trials [48-50]. Hence it will not be wrong to say that we are still in a parallel scenario to manage sepsis-like Hippocrates 4

Journal Pre-proof was. Sepsis is still considered a graveyard for pharmaceutical companies. Additionally, sepsis

patients

either

die

or

if

they

survive,

get

life-long

disability

including

immunosuppression, delirium, increased chances to get infections or even some time patients to have to lose their limbs [51-56]. Hence sepsis research requires new directions for better understanding its pathogenesis and designing new therapeutic molecules for its management. 3. Where to go 3.1. The complement system (CS) during sepsis CS is evolutionarily primitive but one of the primary components of the innate immune system against pathogens [57-60]. Our current knowledge about CS has established that it

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does not only comprise of its circulating protein components described somewhere else [57, 61-63]. Instead complement receptors (CRs) including CR1 (CD35), CR2 (CD21), C5aR1, C5L2 (C5aR2), C3aR play a very crucial role in the regulation of both innate and adaptive (T

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cells and B cells) immunity [64-69]. The human CD4+ T cells also express C5aR1

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intracellularly, that upon activation stimulates NLRP3 inflammasome via the intracellular generation of reactive oxygen species (ROS) inducing the release of IL-1β cytokine [70, 71].

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This IL-1β, in turn, promotes interferon-γ (IFN-γ) production and T helper 1 or Th1 differentiation in an autocrine fashion [71]. In addition to the intracellular expression of

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C5aR1 in human T cells, they also express complement protein C3 intracellularly [72]. This C3 cleaves into C3a and C3b via T cell-expressed protease cathepsin L (CTSL), the tonic

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TCR signaling needs this intracellular C3a. T cells isolated from the patients with

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autoimmune diseases, exhibit higher intracellular C3a levels, that signal to increase the production of pro-inflammatory cytokines including IFN-γ. The inhibition of CTSL activity in T cells prevents this pro-inflammatory phenotype. The role of complement components (C3a and C5a and their cognate receptors) in CD4 +, CD8+, and CD4+CD8+ T cells during sepsis needs to explore. It is well established that C5a component serves as a dark side of the sepsis via exerting its pro-inflammatory by inducing the release of pro-inflammatory cytokines from macrophages, inducing the coagulation, and thus the multi-organ failure and death of the patient [73-75]. However, the inhibition of C5a proves beneficial to the animal models of sepsis and acute respiratory distress syndrome (ARDS) [76]. For example, C5a blockade protects to the cecal ligation and puncture (CLP)-induced septic rats via increasing their survival in the 10-day model [77, 78]. Thus it becomes very challenging to target C5a in sepsis because, in one way it controls the function of T cells and on the other hand, it promotes the pro-inflammatory function, coagulation events, and MODS-associated with sepsis [79, 80]. On the other hand, the decrease in circulating C3 and C4 components of the 5

Journal Pre-proof CS in septic patients accounts for the high risk of DISC and poor prognosis [81, 82]. Hence immune cell and sepsis stage-specific targeting of the complement component is the only option left, otherwise, it has more chances of failure than benefit. Autophagy during sepsis Autophagy is considered one of the several immune mechanisms playing a crucial role in the pathogenesis of inflammation and infectious diseases, described in detail somewhere else [83-87]. Additionally, autophagy also regulates the differentiation, renewal, and homeostasis of both myeloid (dendritic cells (DCs), neutrophils, monocytes/macrophages, and MCs) and lymphoid (B and T cells) immune cells [88]. Typically, immune cells dependent on oxidative

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phosphorylation (OXPHOS) including memory lymphocytes and regulatory T cells (Tregs) for their energy requirement need autophagy for their homeostasis [89-91]. Various intracellular signaling mechanisms controlling the induction of autophagy comprise of 5′

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adenosine monophosphate-activated protein kinase (AMPK), c-Jun N-terminal kinase

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(JNK)/p38 mitogen-activated protein kinase (MAPK) pathways generating ROS and regulating the NF-κB controlled by the activation of various TLRs including TLR4 and

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TLR9 (Fig. 2) [92-94]. The induction of autophagy during sepsis protects the host against MODS via preventing apoptotic cell death of immune cells, maintaining the homeostatic

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cytokine balance between the productions of pro- and anti-inflammatory cytokines, and preserving mitochondrial functions (Fig. 2B) [95-98]. On the other hand, a decrease in during

sepsis

aggravates the

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autophagy

tissue and

organ injury [99,

100].

The

polymorphisms of the autophagy-related gene loci in the IRGM (immunity-related GTPase

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3.2.

family, M) gene are responsible for the sepsis-associated high mortality [101]. However, autophagy starts with the initiation of sepsis, but its flux decreases with its advancement (Fig.2) [98, 102-104]. For example, Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein) is a Class III PI(3)K-associated protein required for microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis (LAP) or noncanonical autophagy (a process by which elements involved in the autophagy conjugate LC3 to phagosomal membranes). The phagocytosis of pathogens and particles

engaging

immunoglobulin-

cell

and

surface

PRRs

including

mucin-domain-containing

TLRs

molecule,

along also

with

known

TIM4 as

(T-cell

Timd4),

a

phosphatidylserine receptor mediating the phagocytosis of dead cells, and FcγR by macrophages triggers LAP (Fig. 2A) [105-111]. LAP controls various immunologic reactions and processes including type 1 interferon (IFN) generation in response to TLR9mediated recognition of DNA-immune complexes, phagocytic clearance of dead cells, and 6

Journal Pre-proof antigen

presentation

[107,

112-115].

LAP

is

an

immunologically

silent

kind

of

phagocytosis of dead cells and produces no inflammatory reaction [116]. However, the deficiency of LAP causes the development of lupus-like inflammatory reaction due to decreased clearance of dead cells [114, 116]. Rubicon also suppresses the autophagosome maturation by negatively regulating the interaction of Beclin-1 (Bcn-1, a mammalian orthologue of yeast Atg6) with PI3KC3/Vps34 (vacuolar protein sorting pathway 34) and UVRAG (UV irradiation resistance-associated gene) or by blocking GTPase Rab7 activation required for endosome maturation, autophagosome formation, maturation, its transportation to along microtubules, and lysosome biogenesis [117-122]. Rubicon inhibits

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autophagy and enhances the apoptotic cell death of hepatocytes along with lipid accumulation in the liver of mice subjected to nonalcoholic fatty liver disease (NAFLD) [123]. Rubicon-/- mice subjected to sepsis exhibit the increased survival and autophagic flux

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in the hearts preventing the cardiac damage without exerting a significant impact on the

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levels of pro-inflammatory cytokines [103]. Various strategies have been used to restore the immune homeostasis via modulating the autophagy during sepsis [124, 125].

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Mitofusin 2 (Mfn2) is an integral GTPase protein of mitochondrial outer membrane that plays a crucial role in the mitochondria outer membrane fusion and forms a bridge between

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mitochondria and endoplasmic reticulum (ER) to transfer the Ca2+ [126-128]. Mfn2 prevents the expansion of ER and the overexpression of all three Unfolded Protein Response (UPR)

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branches (PERK (double-stranded RNA-dependent protein kinase (PKR)-like ER kinase),

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XBP‐ 1 (X-box binding protein 1), and ATF6 (Activating transcription factor 6)) during ER stress [127]. Mfn2 also maintains the mitochondrial coenzyme Q (a key component of mitochondrial respiratory chain involved in the generation of ATP molecules) levels [129]. The splenic CD4+T cells at 24 and 72 hours’ time course undergoing sepsis-associated apoptotic cell death as a result of the inhibition of autophagy show an increased level of Mfn2 [130]. An in vitro study has indicated a decrease in the Mfn2 in Jurkat T cells stimulated with recombinant human HMGB1 (rhHMGB1) induces their apoptosis via increasing the cytosolic Ca2+ and caspases [131]. Thus both low and high levels of Mfn2 prove detrimental to the T cell survival during sepsis. Hence it will be interesting to observe the impact of Mfn2 on other immune cells including macrophages, neutrophils, and dendritic cells (DCs) as the apoptotic death of these cells also contributes to the sepsis-associated immunosuppression. Mfn2 levels decrease in the hepatocytes isolated from both endotoxemic (4-6 h) and CLPinduced septic (12-18 h) mice cause enhanced mitochondrial dysfunction and apoptosis of 7

Journal Pre-proof hepatocytes [132]. Thus Mfn2 levels may have great potential to control the sepsisassociated MODS and needs to be investigated. When the ER stress increases beyond the compensatory capacity of UPR or becomes extensive, the apoptosis of immune cells initiates cell injuries and cell death [133]. The sepsis-associated severe ER stress is responsible for acute lung injury (ALI) and diaphragms contractile dysfunction [133-136]. Cold-inducible RNA-binding protein (CIRP), a highly conserved nuclear protein serving as a damageassociated molecular pattern (DAMP) translocates from the nucleus to the cytoplasm and releases into the peripheral circulation during sepsis [137, 138]. CIRP plasma levels predict the degree of renal injury and cause ALI along with its association with poor prognosis of

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sepsis [136, 138]. CIRP stimulates the release of TNF-α and HMGB1 from macrophages via activating and forming TLR4-MD2 (myeloid differentiation factor 2) complex [136, 137]. Additionally, it also activates NLRP3 inflammasomes and causes vascular endothelial cell

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dysfunction and vascular leakage, edema, aggravated leukocyte infiltration, and cytokine

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(IL-1β) production in the lungs, and an upregulation of adhesion molecules (ICAM-1 (Intercellular Adhesion Molecule 1 or CD54) and E-selectin) on pulmonary endothelial cells

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[139].

The increased circulating levels of CIRP also increase the expression of ICAM-1 on

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neutrophils, and a high infiltration of ICAM-1+ neutrophils into the lungs is responsible for sepsis-induced ALI [140]. These ICAM-1+ neutrophils secrete higher amount of iNOS and

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NETs responsible for Sepsis-associated ALI. The extracellular CIRP-induced during sepsis

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also causes neutrophil reverse transendothelial migration (rTEM) to induce their migration from tissues/organs into the circulation through an increase of neutrophil elastase (NE) and decrease of junctional adhesion molecule-C (JAM-C) [141]. The inhibition of CIRP significantly increases the survival among sepsis mice as compared to control group [140]. All the three UPRs namely, PERK, XBP-1, and ATF6 are increased in sepsis [133, 142-144]. The targeting of ER stress and autophagy during sepsis has been proved beneficial in experimental models of sepsis [143, 144]. ATG16L1 autophagy protein induces autophagy of intestinal epithelial cells (IECs) to protect the enteric Salmonella typhimurium infection and the systemic spread of enteric bacteria causing sepsis [145]. Mice lacking ATG16L1 are more prone to develop enteric bacterial infections and associated systemic inflammation along with bacteremia causing sepsis. Thus knocking on the doors of autophagy may open new avenues to target sepsis. 3.3. The

interaction

between

autophagy,

inflammasomes during sepsis 8

complement

components,

and

Journal Pre-proof The details of the interaction between CS, inflammasomes, and autophagy in host defense have been described recently somewhere else [146]. Drosophila macroglobulin complementrelated (Mcr), a complement ortholog, plays a crucial role in the process of cell death during embryonic development and inflammation by impacting the process of autophagy. Mcr via binding to the Draper (an immune receptor) plays a crucial role in the process of inflammation and the autophagy of macrophages [147]. The process needs attention in the mammalian inflammatory diseases (sepsis). Complement component C3 plays a significant role in the process of autophagy in retinal degeneration as its absence causes a decreased retinal autophagic activity [148]. C3 is highly expressed intracellularly (cytosol) in human

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pancreatic β cells that via interacting with ATG16L1 regulates the autophagy through regulating the autophagosome fusion with lysosomes under inflammatory conditions [149, 150]. For example, the knocking out of C3 in clonal β cells impairs the autophagy and

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promotes their apoptotic cell death upon exposure to palmitic acid and IAPP (Islet amyloid

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polypeptide, also called amylin, a hormone co-stored and co-secreted with insulin) or diabetogenic stress due to the inhibition of the autophagy [149, 151]. The complement

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component C3-based regulation of autophagy through its interaction with ATG16L1 has also been reported to restrict the growth of intracellular bacteria (Listeria monocytogenes) [152].

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However, this is not true for Shigella flexneri and Salmonella typhimurium as they escape this process of growth restriction induced by autophagy in part due to the cleavage of bound C3

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through the action of bacterial outer membrane proteases [152]. Thus complement is also

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controlling the process of autophagy that plays a pivotal role in sepsis and associated multiorgan dysfunction/damage.

The loss of autophagy-related 16-like 1 (Atg16L1) protein increases the production of ROS and

oxidized

mitochondrial DNA (mtDNA) to

enhance the activation of NLRP3

inflammasome and caspase 1 (CASP1) in macrophages that profoundly produce IL-1β and IL-18 (Fig. 2B) [153-156]. The deletion of autophagic protein ATG16L1 has also shown increased

mortality during Chlamydia

pneumoniae

(CP) infection, neutrophilia, and

increased NLRP3 inflammasome activation (increased IL-1β and IL-18) [153, 157]. The loss of ATG16L1 disrupts the recruitment of the Atg12-Atg5 conjugate to the isolation membrane that results in a loss of LC3 conjugation to phosphatidylethanolamine. Consequently, both autophagosome formation and degradation of long-lived proteins have severely impaired in Atg16L1-deficient cells [153]. The autophagy induction reduces the bacterial replication without altering the mortality that can be correlated with a decreased IL1β production during early stages due to the inhibition of inflammasomes, but that increases 9

Journal Pre-proof later

[157].

CP

infection

harnesses

NLRP3/ASC/caspase-1

inflammasome

for

its

intracellular growth, causing an accumulation of lipid droplets in infected macrophages [158]. This also causes increased production of IL-1β due to the inhibition of ATG16L1dependent autophagy. Thus, an increase in autophagy prevents the NLRP3 inflammasome overactivation preventing the exaggerated inflammatory immune response and tissue damage (Fig.

2B).

For

example,

TRIM20

(Tripartite Motif 20) via autophagy degrades

inflammasome components, NLRP3, NLRP1, and pro-caspase 1 [159]. Autophagy also controls the release of IL-1β by targeting the degradation of pro-IL-1β. IL-1β sequesters into autophagosomes and increases the phenomenon of autophagy as rapamycin (an mTOR

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inhibitor) degrades it and inhibits the release of mature IL-1β during endotoxemia [160,

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161]. The inhibition of autophagy increases the release of IL-1β in an NLRP3 inflammasome-dependent manner due to an increased ROS generation [160, 161]. The

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activation of NLRP3 and NLRP4 inflammasomes inhibits autophagy in a beclin1 and PTEN

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(Phosphatase and tensin homolog)-induced putative kinase 1 (PINK1)-dependent manner during the group A streptococcal (GAS) infection responsible for sepsis and hyperoxia with

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an increased ROS generation (Fig. 2B) [162-164].

The enhanced activation of NLRP3 inflammasome during Pseudomonas aeruginosa (P.

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aeruginosa) infection in human macrophages prevents their intracellular killing without affecting the generation of antimicrobial peptides (AMPs), ROS, and NO . [165]. This

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pathogen escape due to the NLRP3 activation increases LC-3 (Microtubule-associated

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protein 1A/1B-light chain 3)-II protein activity and the formation of autophagosomes enhancing autophagy [165, 166]. A deficiency of autophagy-related protein 7 (Atg7) during gram-negative bacterial infection increases the systemic bacterial load to cause bacteremia and sepsis [167]. The deficiency of Atg7 upregulates the NLRC4 inflammasomes and their pro-inflammatory

activity via an exaggerated

release of IL-1β and

pyroptosis of

macrophages (Fig. 2B) [167]. The NLRP6 inflammasome deficiency is also associated with the defective autophagy among intestinal cells causing dysbiosis of intestinal pathogens into the circulation to cause sepsis [168]. Thus autophagy, complement, and inflammasome activation are interrelated processes playing a pivotal role in the sepsis pathogenesis and its outcome [147, 148, 169-171]. For example, autophagy and inflammasomes regulate each other in an opposing manner [172-175]. It will be a novel therapeutic approach to target this interaction between autophagy, CS, and the inflammasomes during sepsis. 3.4. Microbiome during sepsis

10

Journal Pre-proof The microbiome plays a significant role in the pathogenesis of various inflammatory diseases including inflammatory bowel disease (IBD), cancer, allergy, autoimmunity, and neurodegeneration (Fig. 3) [176-181]. The role of microbiota in inflammatory diseases is well established due to its impact on the maturation of gut immune system and the release of several metabolites [short chain fatty acids (SCFAs)] with immunomodulatory and immunoregulatory action [182-189]. Inflammasomes-mediated releases of IL-1β and IL-18 exerts a direct impact on antimicrobial peptide (AMP) production to regulate the gut microbiota and its dysbiosis [190]. The dysregulation of NLRP3 inflammasome enhances the IL-1β production that alters the gut microbiota. The altered gut microbiota enhances the local

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AMP secretion enhancing the immunosuppressive action of regulatory T cells (Tregs) [191]. A higher level of Tregs is also responsible for sepsis-associated immunosuppression [192]. Furthermore, the deficiency of NLRP3 inflammasome dysregulates gut-liver axis and

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induces the dysbiosis of the gut microbes into the circulation, causing the development of

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sepsis [193]. However, NLRP6- and ASC-mediated inflammasome signaling pathways do not affect gut microbiota and thus, the associated systemic innate immune response [194,

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195]. In addition to inflammasomes, complement component C4B (Chido blood group) encoded by C4B gene also influences the diversity of gut microbiota and its dysbiosis via

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escalating complement reaction towards microbiota (Fig. 3) [196]. For example, C4B deficiency and the variations in its gene copy numbers alter the gut microbiota inducing

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autoimmune diseases (systemic lupus erythematosus (SLE)) in mammals [197, 198]. Thus

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the activation of the CS in the gut may also influence the dysbiosis of the gut bacteria and the incidence of sepsis.

The altered immune response during sepsis may alter the gut microbiota. Sepsis also induces the inflammatory and oxidative stress pathway in the intestine, causing the dysbiosis of intestinal microbiota. The fecal samples obtained from patients with sepsis show the predominance of the enterobacteria and reduction of Bacteroides and Bifidobacterium species. The change in microbiota severely reduces the beneficial anaerobic bacteria and breaches the intestinal epithelial integrity [199, 200]. Furthermore, other factors that may change the gut microbiota include hypoxic conditions, intestinal disturbances, disruption in the intestinal epithelial barrier, change in intramural pH values with drug treatment including vasopressors, proton pump inhibitors, parenteral or eternal feeding during critical illness [201]. However, the disruption of gut microbiota by broad-spectrum antibiotics in healthy individuals with induced endotoxemia does not affect systemic innate immunity [202].

11

Journal Pre-proof The experimental and human sepsis translocate the viable gut bacteria into the lungs affected with the acute respiratory syndrome (ARDS) (Fig. 3) [203]. The bronchoalveolar lavage fluid (BALF) obtained from sepsis-associated ARDS patients shows the abundance of gut bacteria that significantly correlates with the severity of sepsis [203]. The level of pulmonary TNF-α in the BALF significantly correlates with the changed lung microbiota dominated by the intestinal microbiota [203]. It would be interesting to observe the gut microbiota translocation and its association with other vital organ injuries including acute kidney injury (AKI) and brain encephalopathy during sepsis. One can speculate that the gut microbiota, their

metabolites,

and

microbial-associated

molecular

patterns

(MAMPs)

including

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peptidoglycan (PGN), can modulate the immune system in distant organs including lungs and liver [204]. For example, the PGN derived from the gut microbe impacts local intestinal immune response (induces the production of AMPs from enterocytes) and the distant

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systemic immunity (induces the systemic immune response in fat-body cells and affects the

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distant neurons for modulating the animal behavior) [205]. The treatment with microbiotaderived SCFAs (acetate, propionate, and butyrate) proves beneficial in improving the renal

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discomfort caused by AKI via epigenetic modulation of the inflammatory process [206]. SCFA treatment further inhibits the maturation of DCs and their capacity to induce the CD4 +

kidney epithelial cells [206].

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and CD8+ T cell-mediated immune response and improves the mitochondrial biogenesis in

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Metagenomic analysis and propidium monoazide (PMA, a DNA chelating agent excluded by

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an undamaged bacterial membrane) have revealed a critical alteration in the whole gut microbiota of patients with sepsis admitted to intensive care units (ICUs) [207, 208]. The altered gut microbiota during acute phase potentially modifies early prognosis. The antibiotic therapy during sepsis further alters the microbiota [209]. The altered gut microbiota further affects the immune response negatively and aggravates the inflammatory damage [189, 201]. Gut-microbiota protects the host during sepsis through inducing T cell-dependent serum immunoglobulin A (IgA) and the high production of IgA secreting plasma cells in the bone marrow (Fig. 3) [210]. The serum IgA binds specifically to the restricted bacterial taxa and prevents their dysbiosis from circulation.

Furthermore,

enrichment with the specific

microbiota increases the levels of antigen-specific IgA, causing the development of resistance towards polymicrobial sepsis [210]. The alteration of the microbiota during sepsis is too conspicuous to use as an early diagnostic marker along with other fecal volatile organic compounds (VOCs) [211]. Fecal VOCs do not reflect only gut microbiota composition but also their metabolic activity and concurrent interaction with the host. The 12

Journal Pre-proof translocation of gram-negative bacteria from the gut induces the production of a source of antigen and the IgG developed against the antigen called murein lipoprotein (MLP), a highly conserved gram-negative outer membrane protein (OMP), provides protection against systemic infection caused by Escherichia coli (E. coli) and Salmonella typhimurium (S. typhimurium) by coating the pathogen and increasing their phagocytosis [212]. The commensal bacteria-derived LPS is a crucial factor to stimulate B1 cells and the maintenance of basal IgM levels [213]. Both these phenomena protect against polymicrobial sepsis. Even mice lacking gut microbiota are more prone to develop Streptococcus pneumoniae (S. pneumoniae) infection and mediated sepsis in comparison to the normal

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mice [214]. The pulmonary macrophages isolated from these gut microbiota deficient mice show the altered stage of immunometabolism, causing defective S. pneumoniae phagocytosis [214]. Previous studies have shown that alteration in immunometabolism of immune cells

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(macrophages, DCs, and T cells) plays a crucial role in the immunopathogenesis of

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inflammation and sepsis [34, 192, 215-218]. Thus targeting microbiota during sepsis will prove beneficial to design novel biomarkers for the early detection of the severity of the

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sepsis and to maintain its prognosis. In this direction, a newer approach called fecal metabolome has a bright future as it provides a functional readout of microbial activity along

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with reflecting the gut microbiome composition. The fecal metabolomic profiling is a novel approach to explore the intestinal microbiota, hots-microbiota interaction, and the impact of

to

explore the inheritance of complex traits [220].

Furthermore,

fecal

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implicated

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gut microbiota on the host phenotype [219, 220]. Fecal metabolomics profiling may also be

microbiota transplantation (FMT) in a small clinical setting is shown to exert beneficial effect against MODS and diarrhea following severe sepsis [221]. Thus targeting gut microbiota during sepsis has a great potential to provide a new direction for sepsis therapeutics. 3.5.

The interaction between autophagy, microbiome, and the CS during sepsis

The impaired autophagy increases the severity of the sepsis and MODS. The impairment in the autophagy in IECs also alters the gut microbiota and reduces the alpha diversity causing the dysregulation of the immune response [222]. Autophagy of IECs is considered an essential component of the host immunity against invasive bacterial infections leading to the sepsis. Autophagy also regulates the generation and the magnitude of type 1 IFNs at the intestinal barrier [223]. The deficiency of specific autophagy protein called ATG16L leads to the generation of type 1 IFNs against gut microbes and thus the protection against 13

Journal Pre-proof the intestinal bacterial pathogen, Citrobacterium rodentium (C. rodentium) [223]. The ATG16L protein is crucial for the attachment of phosphatidylethanolamine (PE) to the LC3 in the process of autophagosome formation [224]. Thus the deficiency of ATG16L can prove beneficial in preventing the intestinal bacterial infections that can lead to the development of sepsis. Hence, autophagy determines the maintenance of gut microbiota and intestinal immunity during sepsis. Further studies are required to design better therapeutic molecules to target sepsis via autophagy and microbiota. A direct relationship between microbiota and CS is yet to identify in sepsis. The CS-microbiome interaction exists in the cases of preterm births [225]. Thus, CS, autophagy, and microbiome interact

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with each other to maintain immune homeostasis. However, this healthy interaction between CS, autophagy, and microbiome is lost during sepsis and proves detrimental to the host.

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4. Future Perspective

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Sepsis is one of the known cause of mortality among patients admitted to ICUs worldwide despite its knowledge to ancient physicians dated back to more than 2500 years. It has seen

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several developments in its pathogenesis and therapeutics. A significant advancement in the field of the immunopathogenesis of sepsis and immunology has occurred in the last 100

al

years. CS is now studied separately. Autophagy has also evolved as one of the mechanisms controlling the immune response [226, 227]. Microbiota is further involved in the

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development and regulation of an effective immune response. These three processes are

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further regulating the other signaling components of innate immunity including TLR signaling (i.e. autophagic lysis of intracellular microbes, called xenophagy that is mediated by the control of the mitochondrial integrity or selective autophagic clearance of aggregated signaling proteins, called aggrephagy) and inflammasome signaling required for effective inflammatory immune response and vice versa [161, 228-234]. TLR-MyDD88-dependent inflammasome activation and the inhibition of autophagy are involved in the pathogenesis of E. coli-induced septic shock due to the activation of the mammalian target of rapamycin complex 1 (mTORC1) [235]. The mTORC1 activation is one of the several signals causing inhibition of the process of autophagy via reflecting the increased amino-acid availability and the activation of the cellular anabolic process [88]. The microbiota further regulates mTOR signaling pathway [236]. The mTOR signaling is involved in the mitochondrial function and its dysregulation also [237, 238]. The mitochondrial dysregulation in the circulating leukocytes of patients admitted to ICUs due to sepsis is reported and may lead to multi-organ dysfunction [239, 240]. Thus newer therapeutics targeting CS, autophagy, and microbiome 14

Journal Pre-proof has a bright future in sepsis research due to their multimeric effects on different components of the immune system that include inflammasomes and immunometabolism. The sepsis roadmap started with immunotargeting, and the continuous research in the field has opened other avenues converging at a point to potentially target both immune and non-immune components involved in sepsis pathogenesis. Time has come to further investigate these targets to manage sepsis depending on the immunological status of the patient. Author contribution: Kumar V developed the idea, designed the manuscript format, wrote the manuscript, and collected all the literature cited. Conflict of Interest: Author discloses no conflict interest.

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Figure Legends: Figure. 1 Immunopathogenesis of sepsis. The invasion of the host via different routes of exposure including lungs, skin or even

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traumatic injury leads to induction of a pro-inflammatory immune response mediated by

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innate immune cells (i.e. macrophages, neutrophils, mast cells, endothelial cells DCs, and NK cells etc.) to clear the infection. However, the failure to clear the infection by the immune

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system causes the development of sepsis due to the immune dysregulation. Sepsis is clinically

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indicated by the presence of systemic infection along with the life-threatening organ damage due to the induction of disseminated intravascular coagulation (DISC). At later stages, multi-

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organ failure causes death among sepsis patients.

Figure 2. Autophagy during sepsis and its interaction with other pro-inflammatory

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immune signaling mechanisms.

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2A. Induction of LAP or noncanonical autophagy, a non-immunogenic phagocytic event. Autophagy facilitates cell death by acting within engulfing cells to promote LC3-

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associated phagocytosis (LAP) in response to Fcγ-receptor (FcγR), Toll-like receptor (TLR) or phosphatidylserine receptor (PtdSerR) signaling. The process involves the recruitment of the Rubicon- and UVRAG-containing Class III PI(3)K complex allowing sustained VPS34 activity at Laposomes. The process causes a significant deposition of PI(3)P on Laposomes. The PI(3)P mediates the recruitment of downstream ATG proteins to Laposomes and stabilizes the NOX2 complex. Rubicon also stabilizes the NOX2 complex to promote optimal ROS production. The activity of the ATG5–ATG12–ATG16L complex along with ATG3 and ATG4 is essential for LAP due to their involvement in lipidation of LC3. Importantly, the maturation of Laposomes requires the presence of LC3-II. The process of LAP is associated with a decreased inflammation due to the generation of the increased amount of IL-10 and TGF-β and a decreased amount of IL-1 and IL-6. The inhibition of Rubicon during sepsis increases the survival of animals and the autophagic flux in the heart. 2B. The interrelationship 28

Journal Pre-proof between TLR signaling, inflammasomes, and autophagy during sepsis. The activation of TLR signaling due to the recognition of various pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) causes the downstream signaling pathway via MyD88-dependent or MyD88-independent or TRIF-dependent signaling pathway involved in the NF-κB activation and thus the generation of a proinflammatory immune response. This TLR signaling also activates p38MAPK, JNK, and ERK1/2 that block mTORC1 causing the activation of the process called autophagy that has anti-inflammatory action inhibits inflammasome activation, and prevents the development of multi-organ dysfunction syndrome (MODS) at initial stages of sepsis. However, the

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prolonged inflammatory immune response inhibits the process of autophagy that causes increased activation of NLRP3 inflammasomes. The highly active NLRP3 inflammasomes activate Beclin-1 and PINK1 to inhibit the autophagy. However, the Beclin-1 bound to the

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HMGB1 promotes the process of autophagy. The deficiency or the inhibition of autophagy

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proteins Atg16L and Atg7 proves detrimental during sepsis due to profound activation of NLRP3 and NLRC4 inflammasomes causing the release of pro-inflammatory cytokines, IL-

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1β and IL-18. Another autophagy protein called TRIM20 regulates the inflammatory pathway during sepsis via inhibiting the NLRP3, NLRP1, and pro-caspase 1 or pro-CASP1

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components of the inflammasome signaling pathway. The details of autophagy and

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inflammasome interaction are mentioned in the text. Figure 3. The gut microbiome and its impact on sepsis pathogenesis along with its with

complement

component,

and NLRP3

inflammasome.

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interaction

The gut

microbiome maintains immune homeostasis and its alteration is associated with various inflammatory

diseases

including inflammatory bowel disease (IBD) and

allergy etc.

However, an alteration in the functioning of NLRP3 inflammasome is seen in sepsis but its alteration in the gastrointestinal tract (GIT) also causes an altered production of antimicrobial peptides (AMPs) that promotes the dysbiosis of gut bacteria causing the development of sepsis. The altered AMP production also increases the production of Tregs responsible for sepsis-associated immunosuppression. In addition to NLRP3 inflammasome, Complement component C4 also alters the gut microbiota. The dysbiosis of gut bacteria may lead to the development of sepsis. Sepsis also causes the translocation of gut bacteria into the lungs aggravating further the pulmonary damage of sepsis-associated ARDS patients. Further, the gut microbiota-induced production of IgA antibody prevents the dysbiosis of gut bacteria into the circulation and prevents the development of sepsis. See text for detail. 29

Journal Pre-proof 

Sepsis is a disease of medical emergency and in 2017 WHO declared it as a disease of importance



Despite its first recognition by Hippocrates in 430 BC, it is still lacking direct therapeutic target



The immune system plays an important role in the pathogenesis and outcome of sepsis



Complement system can be a novel target during system



Autophagy also plays a very important role in sepsis pathogenesis



Microbiome and its alteration during sepsis plays an important role in the

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All the three systems along with inflammasomes are interrelated with each other and

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can prove a better therapeutic approach for sepsis

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

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pathogenesis of sepsis

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Figure 1

Figure 2

Figure 3