Aspirin (ASA) and dexamethasone (DEX) are widely used anti-inflammatory agents yet their mechanism(s) for blocking polymorphonuclear neutrophil (PMN) accumulation at sites of inflammation remains unclear. Here, we report that inhibition of PMN infiltration by ASA and DEX is a property shared by aspirin-triggered lipoxins (ATL) and the glucocorticoid-induced annexin 1 (ANXA1)-derived peptides that are both generated in vivo and act at the lipoxin A(4) receptor (ALXR/FPRL1) to halt PMN diapedesis. These structurally diverse ligands specifically interact directly with recombinant human ALXR demonstrated by specific radioligand binding and function as well as immunoprecipitation of PMN receptors. In addition, the combination of both ATL and ANXA1-derived peptides limited PMN infiltration and reduced production of inflammatory mediators (that is, prostaglandins and chemokines) in vivo. Together, these results indicate functional redundancies in endogenous lipid and peptide anti-inflammatory circuits that are spatially and temporally separate, where both ATL and specific ANXA1-derived peptides act in concert at ALXR to downregulate PMN recruitment to inflammatory loci.
IntroductionThe process of leukocyte extravasation is crucial to host survival, such that following application of an inflammatory or infectious stimulus, a coordinated series of cellular and vascular responses is set in train: in this scenario, the blood-borne polymorphonuclear leukocyte (PMN) represents the first line of defense in innate immunity as it is the first cell type to rapidly extravasate. 1 PMN trafficking is tightly regulated, such that proinflammatory and anti-inflammatory mediators operate in concert to promote and control the spatiotemporal aspects of PMN extravasation. 2 The full dynamics of this process have yet to be addressed, but it is now well accepted that besides adhesion molecules, cytokines, and chemokines, acting together to direct leukocyte subsets out of the bloodstream, there are counterregulatory mediators that act as stop signals to inhibit PMN extravasation. 3 Annexin 1 (ANXA1), a 37-kDa protein, originally described as a mediator of glucocorticoid actions, is one of these counterregulatory mediators. 4,5 Several pharmacologic investigations have reported that ANXA1 inhibits PMN extravasation in models of acute 6 and chronic inflammation, 7 as well as in models of systemic inflammation. 8 These in vivo investigations, coupled with studies of ANXA1 behavior against human neutrophil activation, have led us to propose the following model: in resting PMNs, ANXA1 is largely localized within the cytosol, 9 but it can be rapidly mobilized on the cell surface when the PMN adheres to endothelial monolayers. 10 Once on the neutrophil plasma membrane, ANXA1 acts in an autocrine/paracrine fashion to reduce cell extravasation. 11 This model is corroborated by studies with passive immunoneutralization strategies 12 as well as by more recent investigations with ANXA1-null PMNs. 13,14 In this context, it is worth noting that the antimigratory effects of ANXA1 have been reproduced by peptides derived from the N-terminal region, both in vivo 15,16 as well as in neutrophil/endothelium interactions in static systems in vitro. 17,18 A new interest in the field has been generated by the observation that ANXA1 and its N-terminal peptides bind to a specific class of G-protein-coupled 7-transmembrane receptors, the formyl-peptide receptors (FPRs). 19 In the mouse, this family comprises several putative members, but only 3 receptor types have been identified in humans. 20 Human FPR is the classic receptor for the chemoattractant formyl-Met-Leu-Phe, whereas the related receptor (ϳ 70% similarity at the nucleotide level) is termed FPRL-1/ALX, indicating that it belongs to the FPR family and that the endogenous anti-inflammatory lipid lipoxin A 4 activates it. 20,21 Of interest, human FPRL-1/ALX-like 1 binds also aspirin-triggered lipoxin A 4 22 and serum amyloid protein A. 20 The third member of the family is FPRL-2, not expressed on neutrophils but on monocytes, which has recently been shown to bind an endogenous peptide derived from heme-binding protein. 23 Using transfected cell systems, ANXA1-derived p...
Contrary to early views, we now know that systemic inflammatory/immune responses transmit to the brain. The microglia, the resident “macrophages” of the brain’s innate immune system, are most responsive, and increasing evidence suggests that they enter a hyper-reactive state in neurodegenerative conditions and aging. As sustained over-production of microglial pro-inflammatory mediators is neurotoxic, this raises great concern that systemic inflammation (that also escalates with aging) exacerbates or possibly triggers, neurological diseases (Alzheimer’s, prion, motoneuron disease). It is known that inflammation has an essential role in the progression of Alzheimer’s disease (AD), since amyloid-β (Aβ) is able to activate microglia, initiating an inflammatory response, which could have different consequences for neuronal survival. On one hand, microglia may delay the progression of AD by contributing to the clearance of Aβ, since they phagocyte Aβ and release enzymes responsible for Aβ degradation. Microglia also secrete growth factors and anti-inflammatory cytokines, which are neuroprotective. In addition, microglia removal of damaged cells is a very important step in the restoration of the normal brain environment, as if left such cells can become potent inflammatory stimuli, resulting in yet further tissue damage. On the other hand, as we age microglia become steadily less efficient at these processes, tending to become over-activated in response to stimulation and instigating too potent a reaction, which may cause neuronal damage in its own right. Therefore, it is critical to understand the state of activation of microglia in different AD stages to be able to determine the effect of potential anti-inflammatory therapies. We discuss here recent evidence supporting both the beneficial or detrimental performance of microglia in AD, and the attempt to find molecules/biomarkers for early diagnosis or therapeutic interventions.
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