Spatiotemporal Orchestration of Macrophage Heterogeneity by Cell Adhesion Molecules

Abstract

Monocyte-derived macrophages (mo-macs) are central regulators of innate immunity and are essential for maintaining physiological homeostasis and host defense. Their functional efficacy relies on precisely coordinated transendothelial migration (TEM) and phenotypic polarization into classically activated (M1) or alternatively activated (M2) macrophages. This review delineates how cell adhesion molecules (CAMs), including integrins, selectins, the immunoglobulin superfamily (IgSF), and cadherins, act as pivotal sensors that orchestrate these spatiotemporal dynamics. CAMs facilitate the multi-step TEM of mo-macs and trigger intracellular signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT), to dictate macrophage plasticity in response to inflammation and the tumor microenvironment (TME). We highlight the dual role of CAMs in driving the pathogenesis of atherosclerosis and cancer while also exploring their potential in bioengineering for regenerative medicine. Elucidating these CAM-dependent regulatory networks not only helps to explain the intrinsic mechanisms underlying immune regulation but also provides a theoretical framework for designing next-generation targeted immunotherapies and personalized clinical interventions for inflammatory diseases and malignancies.

1. Introduction

As pivotal regulatory cells of the innate immune system, monocyte-derived macrophages (mo-macs) are ubiquitously distributed throughout the human body, exerting indispensable roles in maintaining physiological homeostasis and orchestrating host defenses against pathogen invasion [1]. Serving as the immediate precursors, monocytes extravasate from the systemic circulation into peripheral tissues, subsequently differentiating into mature macrophages in response to diverse inflammatory stimuli. These cells are characterized by their multifaceted functional repertoire, including immunomodulation, phagocytosis, and antigen presentation. Beyond classical immunity, mo-macs are integral to fundamental biological processes such as the regulation of endogenous reactive oxygen species (ROS), iron sequestration, and tissue repair [2,3]. A hallmark of macrophage biology is their remarkable plasticity, enabling them to polarize into distinct functional phenotypes—conventionally categorized as classically activated (M1) or alternatively activated (M2) macrophages, depending on the local microenvironmental cues [4]. Thus, the maturation of monocytes into functionally competent macrophages necessitates two finely tuned, sequential events: directed transendothelial migration (TEM) and comprehensive cell polarity remodeling. In the context of infection, these two macrophage phenotypes undergo dynamic transitions in response to physiological shifts to facilitate inflammatory resolution and subsequent tissue repair. Conversely, within the complex landscape of the tumor microenvironment (TME), M1 macrophages typically manifest anti-tumor properties through enhanced antigen presentation and pro-inflammatory signaling, whereas M2-like tumor-associated macrophages (TAMs) frequently promote neoangiogenesis, extracellular matrix (ECM) remodeling, and tumor progression [5]. Consequently, elucidating the molecular determinants governing mo-macs recruitment and polarization is of paramount importance for maintaining homeostasis and developing precision immunotherapies (Figure 1).

Cell adhesion molecules (CAMs) are a family of transmembrane glycoproteins that sense extracellular signals by mediating cell-cell and cell-matrix interactions, triggering cytoskeletal rearrangement and signal transduction. Primarily, CAMs mediate the multi-step process of TEM, guiding the infiltration of mo-macs from the bloodstream into peripheral tissues. Beyond simple tethering, these molecules facilitate stable adhesion at sites of homeostatic perturbation, such as inflammation, and orchestrate subsequent functional responses, including efferocytosis and phagocytic clearance [6]. Emerging evidence further underscores the role of CAMs as pivotal regulators of macrophage polarization. Within inflamed or neoplastic niches, the differential expression and activation of surface CAMs on macrophages modulate intracellular signal transduction, thereby recalibrating systemic immune homeostasis.