Macrophage biology

International research group

Macrophages (Mφ) are key regulators of innate as well as adaptive immunity, and they are essential mediators of chronic inflammatory reactions. Mφ play a critical role in wound healing, tolerance induction, tumour immunity and atherosclerosis (Goerdt 1999). During their recruitment, macrophages encounter various signals that direct their differentiation towards distinct phenotypes and functions. In parallel to the Th1/Th2 dichotomy, two major types of macrophage activation has been described. Classically activated effector macrophages (Mφ1) develop in response to pro-inflammatory stimuli such as Th1 cytokines (IFNγ) or bacterial products (LPS). Classical activation of macrophages is well studied and is characterised by secretion of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 and IL-12, expression of Fcγ receptors I, II and III, a strong oxidative burst, and profound anti-microbial activity (Hamilton 2002). Treatment of macrophages with Th2 cytokines including IL-4, IL-10, IL-13 and transforming growth factor (TGF)-β or with anti-inflammatory mediators such as glucocorticoids (GC) was shown to induce alternatively activated, type 2 macrophages (Mφ2) (Goerdt 1999; Stein 1992; Gratchev 2001). Alternatively activated macrophages were shown to express anti-inflammatory cytokines such as IL-1R antagonist and IL-10, chemokine receptor antagonists such as AMAC-1 (Kodelja 1998), broad-spectrum receptors of innate immunity such as the macrophage mannose receptor (MMR) (Stein 1992), the β-glucan receptor (Mosser 1992), scavenger receptor type I (Geng 1992) the haptoglobin receptor CD163 (Hogger 1998; Schaer 2002) and stabilin-1 (MS-1) (Goerdt 1993; Politz 2002). This molecular repertoire bestows Mφ2 with specific functions such as disposal of soluble and particulate matter and healing.

Upon the introduction of the concept of alternative macrophage activation, attention was given to common traits rather than dissimilarities of Mφ2 induced by different mediators. The induction of widely overlapping Mφ2 phenotypes by IL-4 and IL-13 is explained by the fact that their receptors share the IL4-Ra chain and cause engagement of the STAT6-dependent signalling pathway. Similarly to IL-4 and IL-13, induction of Mφ2 by IL-10 also induces deactivation of the respiratory burst and of inflammatory cytokine production, particularly TNFα (Gordon 2003) signalling (STAT3) and gene expression; IL-10-induced Mφ2, however, differ considerably from IL-4-induced Mφ2 (Lang 2002; Stumpo 2003). These differences are even more pronounced regarding TGF-β and GC. In contrast to the additive effect of GC on the IL-4 induced expression of AMAC-1 (Kodelja 1998; Politz 2000), we have shown previously that the expression of the extracellular matrix (ECM) proteins βIG-H3 and fibronectin (FN) is activated by IL-4 and suppressed to background levels by dexamethasone (Gratchev 2001). Others have shown that GC-induced expression of CD163 is reduced upon treatment of Mφ2 by IL-4, a corresponding difference in haemoglobin uptake was also demonstrated (Schaer 2002). From this we conclude that Mφ2 induced by different mediators may both overlap and serve divergent functions supported by common as well as specific molecular repertoires, respectively.