On the origin of the functional versatility of macrophages

Abstract

Macrophages represent the most functionally versatile cells in the animal body. In addition to recognizing and destroying pathogens, macrophages remove senescent and exhausted cells, promote wound healing, and govern tissue and metabolic homeostasis. In addition, many specialized populations of tissue-resident macrophages exhibit highly specialized functions essential for the function of specific organs. Sometimes, however, macrophages cease to perform their protective function and their seemingly incomprehensible response to certain stimuli leads to pathology. In this study, we address the question of the origin of the functional versatility of macrophages. To this end, we have searched for the evolutionary origin of macrophages themselves and for the emergence of their characteristic properties. We hypothesize that many of the characteristic features of proinflammatory macrophages evolved in the unicellular ancestors of animals, and that the functional repertoire of macrophage-like amoebocytes further expanded with the evolution of multicellularity and the increasing complexity of tissues and organ systems. We suggest that the entire repertoire of macrophage functions evolved by repurposing and diversification of basic functions that evolved early in the evolution of metazoans under conditions barely comparable to that in tissues of multicellular organisms. We believe that by applying this perspective, we may find an explanation for the otherwise counterintuitive behavior of macrophages in many human pathologies.

Nitric Oxide in the Mechanisms of Cell Death and Cytoprotection

“…Specifically, it has been discovered that wound macrophages capable of NO production do not exhibit cytotoxicity towards NO-sensitive cells of the P815 line. Thus, the question arises regarding the necessity and sufficiency of NO for the cytotoxicity of macrophages [32][33][34][35][36]. It should also be noted that NO production can have significant negative effects on macrophages that produce it.…”

Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection

“…Specifically, it has been discovered that wound macrophages capable of • NO production do not exhibit cytotoxicity towards • NO-sensitive cells of the P815 line. Thus, the question arises regarding the necessity and sufficiency of • NO for the cytotoxicity of macrophages [32][33][34][35][36]. It should also be noted that • NO production can have significant negative effects on the macrophages that produce it.…”

The first embryo, the origin of cancer and animal phylogeny. IV. The neoplastic basis for the formation of the innate immune system

“…The evolution of the innate immune system, and of macrophages in particular, has been thought of as a functional repertoire brought on from the unicellular ancestors of animals. The system is believed to have expanded with the evolution of multicellularity and the increasing complexity of tissues and organic systems (Bajgar and Krejcǒva, 2023). What is undeniable is the lack of any embryological basis in discussions of the origin and evolution of the immune system in a multicellular context.…”

“…Such antigens are identified by immune cell receptors called pattern recognition receptors (PRRs) (Akira et al, 2001). Dictyostelium is equipped with a broad array of surface receptors that exhibit substantial homology to mammalian PRRs, such as scavenger receptors (LIMP-2), TLRs (tirA, tirB), leucine-rich repeat receptors (LrrA), and C-type lectin receptors (Bajgar and Krejcǒva, 2023). Activation of such receptors triggers intracellular signaling cascades initiating phagocytosis, phagosome maturation, and bacterial death, as well as cascades related to stress and detoxification responses (Dunn et al, 2018).…”

“…An efficient "digestive" cellular system for ingested material represents only the primary function (Gotthardt et al, 2002) through which phagocytosis extends its functional capacity throughout evolution (Desjardins et al, 2005). A previously formulated hypothesis proposes that many of the characteristics of pro-inflammatory macrophages evolved in the unicellular ancestors of animals, and that the functional repertoire of macrophage-like amebocytes was further expanded with the emergence of multicellularity and the increasing complexity of tissue and organ systems (Bajgar and Krejcǒva, 2023). As argued by Bajgar and Krejcǒva, there is a link between the emergence of embryonic morphogenesis and the expansion of possibilities and complexity of the innate immune system.…”