Macrophages in health and disease

Abstract

The heterogeneity of tissue macrophages, in health and in disease, has become increasingly transparent over the last decade. But with the plethora of data comes a natural need for organization and the design of a conceptual framework for how we can better understand the origins and functions of different macrophages. We propose that the ontogeny of a macrophage-beyond its fundamental derivation as either embryonically or bone marrow-derived, but rather inclusive of the course of its differentiation, amidst steady-state cues, disease-associated signals, and time-constitutes a critical piece of information about its contribution to homeostasis or the progression of disease.

Figure 1.. Fundamental responsibilities of tissue-resident macrophages across tissues

RTMs represent the primary entourage of tissue sentinel phagocytes that help maintain the tissues they inhabit. For example, osteoclasts of the bone eliminate excess bone mass, whereas other macrophages residing within the marrow and splenic macrophages facilitate the generation and elimination of new and dying red blood cells. Whether it be in the CNS, where microglia cooperatively function within neurovascular units, or in the periphery, where perivascular and cardiac macrophages support vascular integrity, RTMs help preserve the vasculature in different tissues. Microglia are also integral for the pruning of neuronal synapses, which also requires them to phagocytose any debris originating from degraded myelin. Alveolar macrophages, like other RTMs in mucosal surfaces, form the immediate innate defense to pathogens.

Figure 2.. Composition of different tissue-resident macrophage populations at the steady state

Depending on the tissue, the ontological composition of the tissue-resident macrophage (RTM) compartment varies, and here, we depict the generation and development of these RTM populations during fetal development and post-birth, based on the accepted paradigm that all RTM are embryonically derived phagocytes. Microglia continue to self-maintain in the brain through interactions with glial cells, like astrocytes, and persist through age with minimal input from peripheral monocytes that infrequently pass the blood-brain barrier to infiltrate the brain parenchyma at the steady state. Alveolar macrophages in the lungs are also capable of preserving their pool of embryonically derived cells during homeostasis, but unlike the brain-resident microglia, tissue-infiltrating monocytes make up an increasing proportion of alveolar macrophages over the course of aging. Therefore, a notable fraction of alveolar macrophages can be derived from monocytes. Intestinal lamina propria macrophages are one such exception of RTMs that are largely comprised of monocyte-derived RTMs. The remarkable turnover of macrophages in the gut require input from blood monocytes.

Figure 3.. The dynamic of ontogenically distinct RTMs at homeostasis and disease-associated mo-macs during disease

At the steady state, tissue-resident macrophages (RTMs) can be comprised of either embryonically derived RTMs or monocyte-derived RTMs, depending on the tissue. Yet, regardless of their development, the two groups are generally phenotypically indistinguishable from one another. However, during disease, injury-associated signals and disease-specific cues prompt the recruitment of blood monocytes and instigate their inflammatory differentiation into disease-associated monocyte-derived macrophages (mo-macs). Although a growing body of work illustrates their more significant contributions to disease and the functionality of tissues during that time, whether these macrophages, at the resolutive phases of disease, simply die off or revert to the bona fide RTM phenotype upon recovery of homeostatic tissue signals is not entirely clear.

Figure 4.. Transcriptional differences that distinguish disease-associated mo-macs from RTMs

The recruitment of monocyte-derived macrophages (mo-macs) during disease reflects a wide variety of inputs, including the lack of steady-state tissue cues that encourage homeostatic differentiation of monocytes into monocyte-derived tissue-resident macrophages (RTMs) and the presence of disease-specific alarmins. As such, their transcriptomic signature distinguishes them from their tissue-resident counterparts, and what remains to be studied more extensively are the functional contributions of these molecular programs to disease progression.

Figure 5.. Overview of the dynamic among RTMs and disease-associated mo-macs in tissues and leveraging it for translational science

(A) Delineating the occupational dynamic of tissues by tissue-resident macrophages (RTMs) (blue) and monocyte-derived macrophages (mo-macs) generated during disease (red) will not only elucidate how their functional differences drive disease in humans but also at what points during disease would response to certain therapies be most appreciated. (B) In order to do so, insight must be driven by precise, scientific questions with translational potential. The advent and continued use of single-cell technologies enable the scientific community to do that, though other methods of highly rigorous profiling efforts could do the same. Broadly, considering the uncertainty of whether mo-macs at disease resolution help revive the local pool of RTMs and the fact that cell states among mo-macs are wide-ranging and diverse, modulating their phenotype—as opposed to trying to deplete them entirely or outcompete them by attempting to forcibly expand surviving RTMs during disease—will be the more practical outlook on new therapeutic designs.