Macrophages: Subtypes, Distribution, Polarization, Immunomodulatory Functions, and Therapeutics

Abstract

Macrophages are heterogeneous immune cells with diverse subtypes and tissue-specific distributions, displaying dynamic polarization states that critically govern their immunomodulatory functions and responses to environmental cues. As key regulators of innate and adaptive immunity, they originate from either embryonic progenitors or bone marrow-derived monocytes and exhibit remarkable plasticity in response to microenvironmental cues. Tissue-resident macrophages (e.g., Langerhans cells, Kupffer cells, microglia) display unique organ-specific functions, while inflammatory stimuli drive their polarization into proinflammatory (M1) or anti-inflammatory (M2) phenotypes along a functional continuum. This review systematically examines macrophage subtypes, their anatomical distribution, and the signaling pathways (e.g., NF-κB, STATs, PPARγ) underlying polarization shifts in acute and chronic inflammation. We highlight how polarization imbalances contribute to pathologies including neuroinflammation, liver fibrosis, and impaired tissue repair, particularly in aging contexts. Furthermore, we discuss emerging therapeutic strategies targeting macrophage plasticity, such as cytokine modulation, metabolic reprogramming, and subtype-specific interventions. By integrating recent advances in macrophage biology, this work provides a comprehensive framework for understanding their dual roles in immune regulation and tissue homeostasis, offering insights for treating inflammatory and age-related diseases through macrophage-centered immunomodulation.

Keywords: immune; inflammation; macrophages; polarization; therapeutics; tissue‐resident macrophages.

FIGURE 1

Developmental origins and heterogeneity of macrophages in the mononuclear phagocyte system. Macrophages from the three distinct origins exhibit tissue‐specific adaptation in different organs. The arrows in the figure indicate differentiation trajectories, highlighting the developmental differences between self‐renewing embryonic macrophages and dynamically replenished monocyte‐derived populations, along with their associated specific markers.

FIGURE 2

Regulation of macrophage polarization by the NF‐κB/STAT pathway. The NF‐κB/STAT axis integrates microenvironmental signals to determine macrophage functional phenotypes. Red and blue arrows highlight the antagonistic interactions between the M1 and M2 pathways, with NF‐κB serving as a central node for inflammatory signaling. This illustrates how signals derived from pathogens or cytokines dynamically alter macrophage function in the context of disease.

FIGURE 3

Macrophage M1/M2 polarization mechanisms. Macrophages polarize into M1 or M2 states via distinct pathways: TLR4 ligands activate M1 through MyD88/TRIF and NF‐κB/IRF3, while cytokines like IL‐4/IL‐13 induce M2 polarization via JAK–STAT signaling. IL‐34 and CSF‐1 also promote M2 activation through intracellular cascades.

FIGURE 4

Macrophage dysfunction in inflammation and disease. Stress triggers DNA damage response via ATM, activating NF‐κB. Senescent cells release SASP, impairing macrophage function—causing polarization imbalance, reduced phagocytosis, and chronic inflammation—linked to wounds, autoimmunity, and cancer.

FIGURE 5

The pathological changes of macrophages in different organs under the state of “inflamaging.” (A) In the brain, remodeling of M1/M2 polarization leads to abnormal neuronal excitation. (B) In the liver, reduced phagocyte function weakens the organ's immune defense capabilities, increasing susceptibility to infections. (C) In skin tissue, an inflammatory tendency manifests as vasodilation and leukocyte infiltration, potentially contributing to the development of chronic dermatological conditions. (D) In skeletal muscle, inflammatory cytokines acting on muscle fibers induce atrophy characterized by reduced muscle volume and diminished strength.