Targeting Macrophage Polarization in Infectious Diseases: M1/M2 Functional Profiles, Immune Signaling and Microbial Virulence Factors

Introduction: An event of increasing interest during host-pathogen interactions is the polarization of patrolling/naive monocytes (MOs) into macrophage subsets (M & Fcy;s). Therapeutic strategies aimed at modulating this event are under investigation. Methods: This review focuses on the mechanisms of induction/development and profile of M & Fcy;s polarized toward classically proinflammatory (M1) or alternatively anti-inflammatory (M2) phenotypes in response to bacteria, fungi, parasites, and viruses. Results and discussion: It highlights nuclear, cytoplasmic, and cell surface receptors (pattern recognition receptors/PPRs), microenvironmental mediators, and immune signaling. M & Fcy;s polarize into phenotypes: M1 M & Fcy;s, activated by IFN-gamma, pathogen-associated molecular patterns (PAMPs, e.g. lipopolysaccharide) and membrane-bound PPRs ligands (TLRs/CLRs ligands); or M2 M & Fcy;s, induced by interleukins (ILs-4, -10 and -13), antigen-antibody complexes, and helminth PAMPs. Polarization toward M1 and M2 profiles evolve in a pathogen-specific manner, with or without canonicity, and can vary widely. Ultimately, this can result in varying degrees of host protection or more severe disease outcome. On the one hand, the host is driving effective M & Fcy;s polarization (M1 or M2); but on the other hand, microorganisms may skew the polarization through virulence factors to increase pathogenicity. Cellular/genomic reprogramming also ensures plasticity of M1/M2 phenotypes. Because modulation of polarization can occur at multiple points, new insights and emerging perspectives may have clinical implications during the inflammation-to-resolution transition; translated into practical applications as for therapeutic/vaccine design target to boost microbicidal response (M1, e.g. triggering oxidative burst) with specifics PAMPs/IFN-gamma or promote tissue repair (M2, increasing arginase activity) via immunotherapy. Monocytes are white blood cells (leukocytes) that help fight off various types of aggressive agents, including microorganisms (bacteria, fungi, viruses, and parasites), and help maintain the healthy balance of the human body. These cells differentiate into specific macrophages in tissues such as the lungs, heart, liver, skin, and brain. The present review focuses on the peculiar cellular properties that macrophages can acquire during the human immune response to infectious diseases. In this regard, it is discussed that macrophages are didactically divided into M1 and M2 subtypes. The first subtype (M1) is responsible for fighting pathogens and causing inflammation. The second subtype (M2) is mainly responsible for healing and repairing damaged tissue. Current knowledge shows that although both subtypes are involved in the same immune response aimed at protecting the human body, these M1 and M2 profiles have different characteristics that have implications for therapeutic measures such as developing specific drugs or vaccines to balance the immune response against a given pathogen and promote a complete cure of the disease. Alongside the therapeutic impacts, this review also looks at the characteristics that allow aggressive microorganisms to counteract the immune response developed by these M1 and M2 cell profiles. It highlights how exactly there can be greater protection or detriment to the human host against a given microorganism when there is a predilection to develop a more abundant immune response from one of the two profiles (M1 or M2).