Sepsis remains one of the deadliest conditions in modern medicine, defined by the third international consensus definitions as an imbalanced host response to infection that leads to organ malfunction. According to figures cited by the World Health Organization, roughly 30 million cases are recorded each year, and sepsis ranks among the leading causes of death in intensive care units worldwide. A newly published review in Cell Signaling, Inflammation & Disease argues that the key to understanding this fatal syndrome may lie in a single, remarkably versatile immune cell: the macrophage. The review, authored by Rajat Atre, Mobbassar Hassan Sk, Gias U. Ahmmed, Arif Siddiquie, Nicole Bender, Luciano Saso and Mirza S. Baig, weaves together evidence on macrophage polarization, immunometabolic reprogramming, autophagy and emerging cell-based and nanoparticle therapies into a unified picture of how these cells shape the course of sepsis from its earliest hours to its late immunosuppressive phase.
Macrophages are frontline sentinels of the innate immune system, present in virtually every tissue of the body. When pathogens invade, they respond with striking speed, engulfing microbes, dead cells and debris while releasing a broad spectrum of signaling molecules that recruit and activate other immune players. What makes them especially compelling as therapeutic targets, the authors emphasize, is their resilience. Studies have shown that during sepsis progression, macrophages are significantly less susceptible to apoptotic cell death than other immune cells such as dendritic cells or lymphocytes. While other components of the immune system collapse under the pressure of overwhelming infection, macrophages persist, continuing to influence the inflammatory environment long after the initial insult.
Central to the review is the concept of macrophage polarization. Traditionally, these cells have been sorted into two broad categories: M1, or classically activated macrophages, which drive the pro-inflammatory phase of sepsis, and M2, or alternatively activated macrophages, which dominate the later immunosuppressive stage. M1 macrophages, triggered by pathogens and endotoxins such as lipopolysaccharide, unleash a flood of pro-inflammatory cytokines and chemokines that fuel the hyper-inflammatory state responsible for much of the early tissue damage. M2 macrophages, by contrast, produce large amounts of interleukin-10, transforming growth factor-beta and other anti-inflammatory mediators that suppress immune activity, promote tissue restoration, support angiogenesis and enable immunological reformation. At least four additional M2-like subtypes, M2a, M2b, M2c and M2d, add further nuance to this spectrum.
The authors are careful to stress that this tidy M1/M2 framework is an oversimplification. Macrophage responses in sepsis are far more dynamic and diverse than fixed categories suggest. Their functional state shifts with the tissue environment, the stage of disease, the type of infection and prevailing metabolic conditions, and individual cells may display pro- and anti-inflammatory characteristics simultaneously. This plasticity is governed by an intricate web of transcription factors, including nuclear factor kappa B, signal transducers and activators of transcription, interferon regulatory factors, activator protein 1 and peroxisome proliferator-activated receptor, along with metabolic pathways involving amino acid and fatty acid metabolism, epigenetic modifications such as methylation and histone alterations. Notably, certain compounds, among them the pentacyclic triterpene LUP20, diosgenin glucoside, lupeol and punicalagin, have been shown to inhibit polarization toward the M1 state and favor M2, thereby damping inflammatory signaling at its transcriptional roots.
One of the review’s most distinctive contributions is its attention to tissue-resident macrophages, the specialized populations that inhabit individual organs and whose behavior is dictated by their local microenvironment. Advances in single-cell RNA sequencing have illuminated their roles in regulating homeostasis, modulating cytokine production, managing iron metabolism, supporting tissue repair and even facilitating neuronal information transfer. In the brain, microglia, the resident macrophages of the central nervous system, have been shown during sepsis to mount exaggerated pro-inflammatory responses that damage Purkinje cells, altering synaptic transmission and impairing motor activity. In the heart, cardiac resident macrophages regulate myocardial homeostasis and monitor mitochondrial dysfunction, a process considered central to sepsis pathology, while also contributing to cardiomyocyte remodeling, anti-fibrotic activity and the modulation of cell death. Alveolar macrophages in the lung lose phagocytic capacity in later stages of sepsis, a decline linked to the immunosuppressive phase that often precedes fibrosis, though epithelial cells can interact with them to support anti-inflammatory functions during the hyperactive early phase.
In the liver, Kupffer cells must balance controlled cytokine production that protects the organ with efficient phagocytosis of pathogens and their toxins, with signaling through NF-kappa B, IRF3 and TLR4 orchestrating these functions. In the kidney, studies have shown that during the initial hyper-inflammatory stage of sepsis, damage and depletion of resident macrophages worsen the condition, and one study reported that a therapeutic peptide accelerated M2 polarization of Ly6C macrophages to combat sepsis. The authors argue that this organ-specific sensitivity to local microenvironments makes tissue-resident macrophages an efficient and largely untapped therapeutic strategy, potentially allowing clinicians to design interventions tailored to specific organ dysfunction rather than applying blunt, systemic treatments.
The review then turns to immunometabolism, an emerging discipline that examines how intracellular metabolic reconfiguration governs immune cell function. Metabolic pathways including glycolysis, lipid metabolism, amino acid metabolism and the tricarboxylic acid cycle play decisive roles in determining how macrophages behave during sepsis, particularly in the acute phase. One of the most clinically significant observations concerns lactate, a well-established marker of sepsis-related mortality. Lactate accumulates when macrophages shift from regular oxidative phosphorylation to increased glycolysis in response to pathogenic attack, a metabolic transformation driven by inflammatory mediators such as cytokines and toxins including peptidoglycan and lipopolysaccharide. In an endotoxemia mouse model, LPS was found to escalate the enzyme G6PD, which participates in the pentose phosphate pathway within macrophages, further illustrating how infection rewires cellular metabolism.
Amino acids and lipids also emerge as promising biomarkers. Septic patients show significantly reduced levels of branched-chain amino acids, and one analysis found that tryptophan, aspartic acid, serine and asparagine decreased while proline, glutamine and alpha-amino-n-butyric acid increased in patients with severe sepsis, a fluctuating pattern that could serve as a prognostic indicator. On the lipid front, beta-oxidation, the core of fatty acid metabolism, has been reported to be significantly affected in sepsis patients, with altered levels of nine fatty acid transport proteins, while septic mice in an in vivo study showed elevated levels of certain fatty acids.
Autophagy, the cellular recycling mechanism that maintains intracellular equilibrium, forms the third pillar of the review. Evidence indicates that autophagy modulates inflammation and immunity in significant ways. When ATG16L1, a protein central to autophagy, is depleted, interleukin-1 beta levels rise in response to endotoxin, suggesting a protective role for autophagy in inflammatory conditions. Mice with impaired autophagy fare worse under LPS challenge than normal animals. Autophagy also regulates migration inhibitory factor, which drives inflammation through AKT and ERK pathways; macrophages with impaired autophagy produce higher levels of reactive oxygen species, which in turn increase MIF and inflammation. The balance between MIF production and macrophage autophagy significantly influences the onset of sepsis. Autophagy further shapes polarization through NF-kappa B signaling, promoting the M2 state in tumors, while its dampening restores NF-kappa B activity and pushes macrophages toward M1. Beyond inflammation, autophagy regulates phagocytosis itself: knocking out ATG7, a crucial enzyme for phagophore formation, in mice compromised both the phagocytic capacity of macrophages and the ability of monocytes to differentiate into macrophages, and impaired autophagy has been linked to intensified macrophage apoptosis, defective NLRP3 inflammasome regulation, LPS escape and the accumulation of dysfunctional phagosomes carrying bacterial elements. By targeting pro-interleukin-1 beta for lysosomal breakdown, macrophage autophagy can limit the release of this inflammatory driver during sepsis.
On the therapeutic frontier, the review surveys macrophage-based cell therapies and nanomedicine, while cautioning that most approaches remain at the early preclinical stage. Conventional sepsis care, timely antibiotics, organ support, fluid replenishment and circulatory consolidation, has not achieved significant success in halting organ dysfunction, prompting interest in strategies that target root causes. In a septic mouse model, a population of TREM2-high macrophages termed Mac1 helped cardiomyocytes recover by foraging malfunctioned mitochondria, suggesting that transfusion of such highly specific macrophages could represent a promising experimental therapy. Cross-talk between macrophages and mesenchymal stromal cells offers another avenue: prostaglandin from MSCs transformed macrophages toward the M2 state, reduced inflammatory responses, improved phagocytic debris clearance, upregulated interleukin-10 and hindered neutrophil migration. Transfusion of human induced pluripotent stem cell-derived macrophages enhanced bacterial clearance and reduced neutrophil infiltration during the immunosuppressive stage, when Staphylococcus aureus infections are common, and synthetic CAR macrophages open further possibilities for modulating phagocytosis and adaptive immune responses.
Nanoparticle strategies add a complementary layer of precision. Exosomes derived from alternatively activated M2 macrophages can carry plasmid DNA encoding anti-inflammatory mediators to M1 macrophages, with specificity arising from VLA4 and LFA1 ligands on the exosomes binding VCAM and ICAM receptors on target cells, potentially reprogramming macrophages and resolving cytokine storms. Liposomes loaded with an antimicrobial peptide and cathepsin B mRNA enabled macrophages to eradicate multidrug-resistant bacteria prominent during immunosuppression, while guanabenz-encapsulated liposomes boosted macrophage anti-inflammatory activity through eIF2alpha-dependent and independent pathways, lowering interleukin-1 beta, tumor necrosis factor alpha and interleukin-6. Macrophage membrane-coated nanoparticles have delivered antimicrobial LL37 plasmid DNA, turning macrophages into continuous producers of anti-pathogenic agents, and magnetic nanoparticles bound to specific peptides or antibodies improve detection and visualization of pathogenic load. The authors conclude that immunometabolism, autophagy modulation, tissue-specific targeting and nanomedicine should be viewed as complementary approaches rather than competing strategies, and that safety concerns, patient variability, treatment timing and the need for precise target-specific delivery must be resolved before these experimental therapies can enter routine sepsis care.
Subject of Research: The roles of macrophage polarization, immunometabolism, autophagy and emerging macrophage-targeted therapies in sepsis
Article Title: Macrophages in the crossfire of sepsis: deciphering immunometabolic reprogramming, autophagy, and novel immunomodulatory therapeutic strategies
Article References: Atre, R., Sk, M. H., Ahmmed, G. U., Siddiquie, A., Bender, N., Saso, L., & Baig, M. S. (2026). Macrophages in the crossfire of sepsis: deciphering immunometabolic reprogramming, autophagy, and novel immunomodulatory therapeutic strategies. Cell Signaling, Inflammation & Disease, 1(1), Article 3. https://doi.org/10.1186/s44505-026-00003-z
Image Credits: AI Generated
DOI: 10.1186/s44505-026-00003-z
Keywords: sepsis, macrophages, M1 and M2 polarization, immunometabolism, autophagy, tissue-resident macrophages, cytokine storm, nanoparticles, cell therapy, inflammation, organ dysfunction, biomarkers
News Source: Kristina Jarvis. (October 28, 2026). Macrophages Take Center Stage in the Battle Against Sepsis. Scienmag.
