Functional plasticity of macrophages: reversible adaptation to changing microenvironments

Abstract

There has been substantial research activity in the past decade directed at phenotyping macrophage lineages and defining macrophage functional subsets or patterns of activity. The emphasis over the past 2-3 years has been to divide macrophage functional patterns into type 1 (Th1-driven) or type 2 (Th2-driven) functions. However, a huge array of environmental factors (including cytokines, chemokines, pattern recognition receptors, hormones) differentially regulates macrophage response patterns, resulting in the display of numerous distinct, functional phenotypes. Upon stimulation, a macrophage does not display just a single set of functions but rather displays a progression of functional changes in response to the progressive changes in its microenvironment. The remarkable ability of monocytes and tissue macrophages to adapt to changes in their microenvironment challenges the thesis that macrophages displaying unique tissue-specific or response-specific, functional patterns represent distinct lineages. With the exception of mature osteoclasts and mature dendritic cells, evidence supporting stable differentiation as the basis for macrophage functional heterogeneity is equivocal. The concept of whether macrophages develop into functional subsets as opposed to continuously adapting their functional pattern in response to the changing environment of a progressive inflammatory response is important to resolve from the perspectives of therapeutic targeting and understanding the role of macrophages in disease pathogenesis.

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

“…Alternatively activated macrophages, as distinct from classically activated macrophages, promote wound healing, and macrophages are capable of switching phenotypes under different stimuli. 40 However, 14S,21R-diHDHA did not affect arginase-1 expression under IL-4 stimulus ( Figure 6), a property of alternatively activated macrophages, suggesting that 14S,21R-diHDHA does not act on the macrophage switching to an alternative phenotype. 14S,21R-diHDHA increased IL-10 expression by db/db macrophages under LPS stimulation (Figure 6), suggesting that the recovery of diabetic prohealing functions by 14S,21R-diHDHA may involve augmenting IL-10 generation.…”

“…These results indicate that 14S,21R-diHDHA enhanced the anti-inflammatory functions of db/db macrophages. We also assessed the effect of 14S,21R-diHDHA on IL-4-induced alternative activation, 40 which results in a prohealing phenotype in macrophages and characteristically involves arginase-1 expression. 14S,21R-diHDHA did not affect this type of activation of macrophages under the in vitro conditions used in the present study ( Figure 6C).…”

The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases

“…However, as arginase activity was lower in R17 than DA following stimulation with LPS, the MF activation phenotypes cannot be readily classified into the simplistic 'classically' or 'alternatively' activated macrophage categories. 30 One issue that remains to be resolved is whether the APLEC gene products act as receptors for all the various microbial stimulants. Non-exclusive alternatives include that they may modulate responses to the different adjuvants in other ways, for example, through effects on the resultant intracellular signaling pathways or through binding of induced endogenous danger-associated molecular patterns.…”

Mesenchymal stem cells promote macrophage polarization toward M2b-like cells

“…The ratio of IL-10 to TNF or IL-12 is often used to distinguish M1 from M2 MΦs [16,17]. Although more activation profiles have been identified for MΦs in vivo [18,19], M1, M2a and M2b are the best described functional states. According to Edwards et al, these activation states can be generated in vitro by applying the appropriate inductors: TLR-ligands, such as LPS, together with IFN for M1, IL-4 or IL-13 for M2a and LPS together with immune complexes or apoptotic cells for M2b MΦ phenotypes [9,13].…”