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Background A sustained inflammatory response following spinal cord injury (SCI) contributes to neuronal damage, inhibiting functional recovery. Macrophages, the major participants in the inflammatory response, transform into foamy macrophages after phagocytosing myelin debris, subsequently releasing inflammatory factors and amplifying the secondary injury. Here, we assessed the effect of macrophage scavenger receptor 1 (MSR1) in phagocytosis of myelin debris after SCI and explained its possible mechanism. Methods The SCI model was employed to determine the critical role of MSR1 in phagocytosis of myelin debris in vivo. The potential functions and mechanisms of MSR1 were explored using qPCR, western blotting, and immunofluorescence after treating macrophages and RAW264.7 with myelin debris in vitro. Results In this study, we found improved recovery from traumatic SCI in MSR1-knockout mice over that in MSR1 wild-type mice. Furthermore, MSR1 promoted the phagocytosis of myelin debris and the formation of foamy macrophage, leading to pro-inflammatory polarization in vitro and in vivo . Mechanistically, in the presence of myelin debris, MSR1-mediated NF-κB signaling pathway contributed to the release of inflammatory mediators and subsequently the apoptosis of neurons. Conclusions Our study elucidates a previously unrecognized role of MSR1 in the pathophysiology of SCI and suggests that its inhibition may be a new treatment strategy for this traumatic condition.

Tuberculosis (TB) is a leading cause of death worldwide following infection with (Mtb), with 1.5 million deaths from this disease reported in 2018. Once the bacilli are inhaled, alveolar and interstitial macrophages become infected with Mtb and differentiate into lipid-laden foamy macrophages leading to lung inflammation. Thus, the presence of lipid-laden foamy macrophages is the hallmark of TB granuloma; these Mtb-infected foamy macrophages are the major niche for Mtb survival. The fate of TB pathogenesis is likely determined by the altered function of Mtb-infected macrophages, which initiate and mediate TB-related lung inflammation. As Mtb-infected foamy macrophages play central roles in the pathogenesis of Mtb, they may be important in the development of host-directed therapy against TB. Here, we summarize and discuss the current understanding of the alterations in alveolar and interstitial macrophages in the regulation of Mtb infection-induced immune responses. Metabolic reprogramming of lipid-laden foamy macrophages following Mtb infection or virulence factors are also summarized. Furthermore, we review the therapeutic interventions targeting immune responses and metabolic pathways, from , and clinical studies. This review will further our understanding of the Mtb-infected foamy macrophages, which are both the major Mtb niche and therapeutic targets against TB.

Foamy macrophages and microglia containing lipid droplets (LDs) are a pathological hallmark of demyelinating disorders affecting the central nervous system (CNS). We and others showed that excessive accumulation of intracellular lipids drives these phagocytes towards a more inflammatory phenotype, thereby limiting CNS repair. To date, however, the mechanisms underlying LD biogenesis and breakdown in lipid-engorged phagocytes in the CNS, as well as their impact on foamy phagocyte biology and lesion progression, remain poorly understood. Here, we provide evidence that LD-associated protein perilipin-2 (PLIN2) controls LD metabolism in myelin-containing phagocytes. We show that PLIN2 protects LDs from lipolysis-mediated degradation, thereby impairing intracellular processing of myelin-derived lipids in phagocytes. Accordingly, loss of Plin2 stimulates LD turnover in foamy phagocytes, driving them towards a less inflammatory phenotype. Importantly, Plin2 -deficiency markedly improves remyelination in the ex vivo brain slice model and in the in vivo cuprizone-induced demyelination model. In summary, we identify PLIN2 as a novel therapeutic target to prevent the pathogenic accumulation of LDs in foamy phagocytes and to stimulate remyelination.

Mycobacterium tuberculosis (MTB) is one of the most successful pathogens in human history and remains a global health challenge. MTB has evolved a plethora of strategies to evade the immune response sufficiently to survive within the macrophage in a bacterial-immunological equilibrium, yet causes sufficient immunopathology to facilitate its transmission. This review highlights MTB as the driver of disease pathogenesis and presents evidence of the mechanisms by which MTB manipulates the protective immune response into a pathological productive infection.

The progression of human tuberculosis (TB) to active disease and transmission involves the development of a caseous granuloma that cavitates and releases infectious Mycobacterium tuberculosis bacilli. In the current study, we exploited genome‐wide microarray analysis to determine that genes for lipid sequestration and metabolism were highly expressed in caseous TB granulomas. Immunohistological analysis of these granulomas confirmed the disproportionate abundance of the proteins involved in lipid metabolism in cells surrounding the caseum; namely, adipophilin, acyl‐CoA synthetase long‐chain family member 1 and saposin C. Biochemical analysis of the lipid species within the caseum identified cholesterol, cholesteryl esters, triacylglycerols and lactosylceramide, which implicated low‐density lipoprotein‐derived lipids as the most likely source. M. tuberculosis infection in vitro induced lipid droplet formation in murine and human macrophages. Furthermore, the M. tuberculosis cell wall lipid, trehalose dimycolate, induced a strong granulomatous response in mice, which was accompanied by foam cell formation. These results provide molecular and biochemical evidence that the development of the human TB granuloma to caseation correlates with pathogen‐mediated dysregulation of host lipid metabolism.

Lung alveolar macrophages (AMs) are in the first line of immune defense against respiratory pathogens and play key roles in the pathogenesis of ( ) in humans. Nevertheless, AMs are available only in limited amounts for studies, which hamper the detailed molecular understanding of host- interactions in these macrophages. The recent establishment of the self-renewing and primary Max Planck Institute (MPI) cells, functionally very close to lung AMs, opens unique opportunities for studies of host-pathogen interactions in respiratory diseases. Here, we investigated the suitability of MPI cells as a host cell system for infection. Bacterial, cellular, and innate immune features of MPI cells infected with were characterized. Live bacteria were readily internalized and efficiently replicated in MPI cells, similarly to primary murine macrophages and other cell lines. MPI cells were also suitable for the determination of anti-tuberculosis (TB) drug activity. The primary innate immune response of MPI cells to live showed significantly higher and earlier induction of the pro-inflammatory cytokines TNFα, interleukin 6 (IL-6), IL-1α, and IL-1β, as compared to stimulation with heat-killed (HK) bacteria. MPI cells previously showed a lack of induction of the anti-inflammatory cytokine IL-10 to a wide range of stimuli, including HK . By contrast, we show here that live is able to induce significant amounts of IL-10 in MPI cells. Autophagy experiments using light chain 3B immunostaining, as well as LysoTracker labeling of acidic vacuoles, demonstrated that MPI cells efficiently control killed by elimination through phagolysosomes. MPI cells were also able to accumulate lipid droplets in their cytoplasm following exposure to lipoproteins. Collectively, this study establishes the MPI cells as a relevant, versatile host cell model for TB research, allowing a deeper understanding of AMs functions in this pathology.

Tuberculosis (TB) pathology involves complex immune responses within granulomatous lesions. Using single-cell RNA sequencing, we characterized the cellular compositions of necrotizing granulomatous lesions that developed in the lungs of Mycobacterium tuberculosis -infected C3HeB/FeJ mice. We identified 11 distinct major cell types, including phagocytes such as neutrophils and macrophages, and T cells, natural killer cells, B cells, dendritic cells, and plasmacytoid dendritic cells. Among T cells, particularly, Pdcd1 + γδ T cells were detected in necrotizing granulomatous lesions, suggesting their potential role in the pathogenicity of M. tuberculosis . Within the macrophage populations, we identified a cluster with significantly higher Plin2 expression compared to other clusters, whose transcriptomic profile was consistent with that of foamy macrophages. A subset of the Plin2 -expressing macrophages was identified as a major source of Ifnb1 and Cxcl1 , suggesting their involvement in type I interferon signaling and neutrophil recruitment. Furthermore, we identified Flrt2 , Hyal1 , and Mmp13 as novel molecular markers of Plin2 -expressing macrophages, which were localized to the peripheral rim regions of necrotizing granulomas. In conclusion, our results provide the immune landscape of necrotizing granulomas and reveal novel functional states of macrophages contributing to TB pathogenesis.

Non-tuberculous mycobacteria infections, including Mycobacterium avium , are increasingly recognized as a growing public health concern, even among immunocompetent individuals. These infections are a significant cause of chronic pulmonary disease, and they are characterized by the formation of foamy macrophages (FMs) that facilitate bacterial persistence. Previously, we reported that apoptosis inhibitor of macrophage (AIM), a protein secreted by macrophages, promotes lipid droplet accumulation in M. avium -infected macrophages. However, the precise role of AIM in modulating immune responses remains unclear. This study aimed to elucidate the effect of AIM on FM formation, bacterial burden, and immune response in M. avium -infected mice by comparing AIM knockout (KO) mice with wild-type mice. Histological analysis revealed a reduction in FM formation in AIM KO mice, accompanied by decreased lipid droplet accumulation and altered expression of lipid metabolism-related genes. Furthermore, AIM KO mice exhibited a reduced bacterial load in the lungs, highlighting decreased cytokine production, including IL-1β, compared to wild-type mice. In addition, the analysis of the immune cells of AIM KO mice using flow cytometry revealed an increase in M1 macrophages and IFN-γ-producing T cells, as well as a decrease in M2 macrophages and interleukin 10 (IL-10)-producing T cells. The reduced expression of CD36 and PD-L1 in macrophages from AIM KO mice further supports the skewing toward an M1 phenotype. In vitro experiments with bone marrow-derived macrophages (BMDMs) confirmed reduced bacterial growth and lipid droplet formation in AIM KO BMDMs, which was restored by AIM and IL-10 treatment. These findings suggest that AIM contributes to the promotion of FM formation by establishing an immunosuppressive environment that promotes the establishment of M. avium through IL-10 production.

Pathogens trigger metabolic reprogramming, leading to the formation of foamy macrophages (FMs). This process provides a favorable environment for bacterial proliferation and enables bacteria to evade immune killing. To elucidate the mechanisms by which pathogens escape immune surveillance and elimination via the formation of FMs. We constructed a FM model using monocyte-derived macrophages (MDMs) that were incubated with oxidized low-density lipoprotein (oxLDL). Subsequently, we employed bulk RNA-sequencing (bulk RNA-seq) to comprehensively analyze the immune responses in MDMs and FMs against ( ) infection in samples from 10 healthy individuals. We found that CXCL13, a component of the cytokine-cytokine receptor interaction pathway, was specifically upregulated in infected MDMs, when compared with infected FMs. Significantly, further functional analyses revealed that treatment with CXCL13 could enhance the expression of CXCR5, thereby promoting lymphocyte migration and secretion of antimicrobial proteins. Additionally, NLRP12 was found to be specifically and highly expressed in the NOD-like receptor signaling pathway, which was enriched in infected FMs. In macrophages, infection increased CXCL13 expression via NF-κB signal pathway. Conversely, in FMs, mycobacteria induced upregulation of CXCL13 was suppressed by NLRP12 through the inhibition of p52 factor expression. In conclusion, the NLRP12/NF-κB/CXCL13 axis is crucial for the immune response of FMs after mycobacterial infection. These findings contribute to a deeper understanding of the pathological mechanisms of mycobacterial infection.

[This corrects the article DOI: 10.3389/fimmu.2020.00910.].[This corrects the article DOI: 10.3389/fimmu.2020.00910.].