Dallas, Texas,United States. Internal MedicineRheumatologyImmunology Institution: Systemic lupus erythematosus SLE is a heterogeneous group of autoimmune disorders defined by a consensus of clinical and laboratory criteria.
Much of the pathophysiology and therapy of SLE has focused on autoimmune B and T cells of the adaptive immune system. Recently, the role of macrophages, part of the innate immune system, in SLE pathogenesis has gained attention.
The field of immunology in general has recently changed in the way Jacob n brys it approaches macrophages. Rather than viewing them as a single, concrete Jacob n brys, it has become clear that different subpopulations of macrophages contribute to various immune and non-immune processes. Such a nomenclature may provide an ideal framework from which to study macrophage pathogenesis in SLE. Studies suggest that M1 subtype macrophages play an important inflammatory role in SLE pathogenesis.
Further, apparently reduced populations of M2a and M2c subtype macrophages may contribute to the lack of anti-inflammatory activity apparent in Jacob n brys disease. M2b subtype macrophages may actually have a role in causing disease directly.
Regulatory macrophages have yet to be explored thoroughly in SLE, though the presence of a few of their markers may mean that they are active in suppressing SLE-related inflammation. Recently, focus has shifted to the role of macrophages — part of the innate immune system — in SLE pathogenesis. What was once considered a monolithic group of waste collectors is now a heterotypic, heterogeneous population of multipurpose cells.
In much the same way as effector T cells have been parsed and scrutinized for their diversity, macrophages are now being subdivided and classified anew. These new classes have important and Jacob n brys relevant roles in a number of disease states.
However, the new nomenclature has yet to be used to study macrophage pathogenesis specific to SLE. In this review, we first give an overview of the latest macrophage nomenclature. We further discuss, per observations in the literature, the roles of various macrophage subtypes in the pathogenesis of SLE based on our current understanding of the disease. In the last several years, macrophages have been increasingly subdivided and categorized based on apparent activity, location, and cell surface marker expression.
One of the most useful classifications to emerge has been that of Mantovani et al. Other subdivision methods as cited in the table help to round out a subpopulation-based view of macrophage classification. These subdivisions can make reversible changes that respond to the micro-environmental milieu. While they do not necessarily represent distinct populations of cells, they do represent a useful functional nomenclature by which broad Jacob n brys may be made into their function in disease.
As of yet, little work has Jacob n brys done to establish what the individual role of these macrophage subtypes might be in Jacob n brys pathogenesis. We undertake here a review of possible macrophage subtype contributions to disease based on current leads. Type 1 immune response, mediated by T H 1 cells, refers to the inflammatory response that clears viral, bacterial, and protozoan infections.
Type 2 immune response, mediated by T H 2 cells, refers to a response that is more efficacious in clearing parasites. This classification has been extraordinarily useful in the systematic study of the Jacob n brys immune response, and it has grown to include other subsets of helper T cells. Not surprisingly, helper T cells are not the only player in any given immune response.
It Jacob n brys since been discovered that distinct populations of macrophages, termed M1 and M2 cells, facilitate and control type 1 and type 2 immune responses, respectively. Just as T H 1 cells facilitate inflammation and help clear typical pathogens, M1 macrophages are pro-inflammatory and assist in controlling infections by expressing reactive oxygen species ROScomplement and immunoglobulin receptors, and inflammatory cytokines.
On the other hand, M2 macrophages express a different set of cytokines that appears related to type 2 immune responses and anti-inflammatory processes. SLE is a markedly inflammatory disease in the absence of appropriate pathogens.
One important theory in the pathogenesis of SLE is that inflammatory M1 macrophages could be out of control. M1 macrophages are classical phagocytic, inflammatory Jacob n brys that act in delayed-type type IV hypersensitivities, tumor resistance, and type 1 inflammation.
They have long been believed to be a source of pathology in SLE. Jacob n brys include CD86 Sui et al. These markers are important in macrophage activation state, chemotaxisand general pro-inflammatory activity. M1 macrophages are also favored by the milieu they reside in. Predisposing genetic factors also support the M1 dominance hypothesis. Indeed, recent work in models of atherosclerosis — which occurs frequently in patients with SLE — showed the importance of the M1 subtype in instigating inflammation as well as M2 macrophages in reducing it Feig et al.
While HMG-CoA reductase inhibitors may be expected to have multiple unrelated effects, they have also been shown to improve lupus symptoms by unknown mechanisms van Leuven et al.
Further, CCL5 antagonists, which might be expected to blunt renal injury because they block M1 actions on cytotoxic T and NK cells, actually accentuate mouse models of renal damage even in the absence of lymphocyte infiltration Anders et al. These findings Jacob n brys a more nuanced picture of macrophage subpopulation contribution to SLE. A recent review by Anders and Ryu suggested that increased M1 as well as M2 macrophage subpopulations in various kidney pathologies could explain various findings and influence disease course.
M2 macrophages are generally divided into a, b, and c subtypes. They appear to perform separate tasks in inflammation and are designated by different monikers in different publications.
M2a macrophages are referred to as alternatively activated or profibrotic; M2b as regulator or T H 2-related; and M2c as deactivated, remodeling, or anti-inflammatory.
Each may have its Jacob n brys role in the pathology of SLE. As discussed above, all M2 macrophages produce an IL IL ratio opposite of M1 macrophages Mantovani et al. M2a macrophages have been characterized as profibrotic Anders and Ryu, Fibrosis is a common finding in lupus and has Jacob n brys attributed to macrophage function Davis and Lennon,though not definitively attributed to any particular macrophage subpopulation.
M2a macrophages do not appear to be Jacob n brys major macrophage subpopulation in SLE. While data only exists for a few M2a markers, the expression of these markers uniformly decreased in human SLE peripheral macrophages, as highlighted in Table 1.
Deliberate expansion of M2a macrophages is one promising therapeutic approach. M2b macrophages are considered an immunity-regulating macrophage subtype that is associated with SLE and activated by immune complexes.
The Notch-1 signaling further caused a lupus-like phenotype. Indeed the surplus of unphagocytosed immune complexes ICs that occur in SLE are known to be inducers of M2b macrophages. TLR signaling is also important in renal pathology Pawar et al. M2b macrophages are known to produce nonspecific inflammatory factors that are elevated in peripheral SLE macrophages.