Macrophage polarization refers to the process by which macrophages can produce two distinct functional phenotypes: M1 or M2. The balance between both strongly affects the progression of inflammatory disorders. Here, we review how redox signals regulate macrophage polarization and reprogramming during acute inflammation. In M1, macrophages augment NADPH oxidase isoform 2 (NOX2), inducible nitric oxide synthase (iNOS), synaptotagmin-binding cytoplasmic RNA interacting protein (SYNCRIP), and tumor necrosis factor receptor-associated factor 6 increase oxygen and nitrogen reactive species, which triggers inflammatory response, phagocytosis, and cytotoxicity. In M2, macrophages down-regulate NOX2, iNOS, SYNCRIP, and/or up-regulate arginase and superoxide dismutase type 1, counteract oxidative and nitrosative stress, and favor anti-inflammatory and tissue repair responses. M1 and M2 macrophages exhibit different metabolic profiles, which are tightly regulated by redox mechanisms. Oxidative and nitrosative stress sustain the M1 phenotype by activating glycolysis and lipid biosynthesis, but by inhibiting tricarboxylic acid cycle and oxidative phosphorylation. This metabolic profile is reversed in M2 macrophages because of changes in the redox state. Therefore, new therapies based on redox mechanisms have emerged to treat acute inflammation with positive results, which highlights the relevance of redox signaling as a master regulator of macrophage reprogramming.

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Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective

Itaconate is a lysosomal inducer that promotes antibacterial innate immunity.

Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine

Abstract Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages. By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB–Irg1–itaconate signalling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium. TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32–BLOC3 system into the Salmonella -containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella , a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB’s role in autophagy-mediated pathogen degradation. Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella Typhimurium burden in macrophages in vitro and in vivo. 

/pdf/tfeb-induces-mitochondrial-itaconate-synthesis-to-suppress-2wc61gdb.pdf

TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages

The immune response of the host towards foreign body, especially in the form of giant cell reaction against the implanted materials, is a vital factor for determining the repair outcome of bone defect. Biomaterials with good immunomodulatory capacity and suitable degradation may promote the regeneration of bone defect and osteointegration with the host. Small intestine submucosa (SIS), a decellularized material, has been shown to possess a property for inducing the M2 phenotype of macrophages. Our findings suggested that the SIS hydrogel could induce the macrophages to polarize into mixed M1/M2 phenotypes, and such phenotypes have enhanced the migration and tube formation of angiogenesis-associated cells in vitro , whilst having a mild effect on osteoclastogenesis and osteogenesis. Experiment with a rat model for critical-sized bone defect regeneration further demonstrated that the composite BMP-2@SIS hydrogel could sequentially activate M1 and M2 macrophages and promote early-stage angiogenesis, which altogether expedited final bone defect regeneration. 

Accelerated bone defect regeneration through sequential activation of the M1 and M2 phenotypes of macrophages by a composite BMP-2@SIS hydrogel: An immunomodulatory perspective

Rui Santalla Mendez

Papers

Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages.