[Mycobacterium] infection causes granulomas composed mainly of M1 and M2 macrophages that allow detection of the bacteria. Histological analysis [by KYOTO UNIVERSITY researchers] of granulomas caused by Mycobacterium bovis [bacillus Calmette-Guerin ]in guinea pigs revealed that neutrophils [expressing S100A9 ] bordered M2 within the multilayered granulomas. S100A9-deficient murine neutrophils abrogated M2 polarization, which was highly dependent on COX-2 signaling in neutrophils.

The interaction of immune cells determines the extent of inflammation, including the time of intensity and duration. Granulomas are spherical structures comprising densely packed macrophages and represent a hallmark of several chronic inflammatory diseases, including tuberculosis, sarcoid, and Crohn’s disease. Histological analyzes have revealed that in addition to other immune cell types, including T- and B-lymphocytes and neutrophils, a significant cellular fraction of persistently activated macrophages [epithelioid cells] accumulates in granulomas. Intracellular interactions within granulomas drive effective inflammatory responses against pathogens or infectious agents.

However, such inflammation persists for extended periods of time. Macrophages are subdivided into M1[inflammatory] and M2[anti-inflammatory] according to their ability to differentiate upon stimulation with cytokines and microbial molecules, with the L-arginine-hydrolyzing enzyme arginase-1 (Arg1) specifically expressed in M2.

In the case of Mycobacterium tuberculosis infection, anti-inflammatory M2 macrophages promoted bacterial survival by suppressing NO production through Arg.1-dependent competitive substrate depletion.

Accumulation of S100A9 (A9) in the necrotic core of granulomas controls initial granuloma formation. A9 is expressed at low levels in monocytes and macrophages, while it is present at high levels in neutrophils, where it is found only as a heterodimer complexed with S100A8 (A8). A9 expressed on neutrophils is critical for M2 polarization of macrophages Granulomas contain stratified M1-type epithelial cells, which serve as cellular and immunological barriers for internal containment of bacteria. A9 forms an active heterodimer with A8 (calprotectin) and is released from inflamed and damaged cells. Extracellular calprotectin acts as an alarmin that activates the innate immune system. A9 promotes PGE synthase, which catalyzes the synthesis of PGE2 in neutrophils.

A9 is necessary for increased PGE2 production. Regarding the COX-2-PGE2 axis in M2 polarization of macrophages, neutrophil COX-2 was found to be critical for M2, but not M1, macrophages, which are entirely dependent on A9 protein.

The A9/Cox-2 pathway promotes PGE2 production in neutrophils

SOURCE: Immunology Inflammation APRIL 2023