Airway epithelial cells and macrophages participate in inflammatory responses to external noxious stimuli, which can cause epithelial injury. Upon injury, epithelial cells and macrophages act in... Show moreAirway epithelial cells and macrophages participate in inflammatory responses to external noxious stimuli, which can cause epithelial injury. Upon injury, epithelial cells and macrophages act in concert to ensure rapid restoration of epithelial integrity. The nature of the interactions between these cell types during epithelial repair is incompletely understood. We used an in vitro human coculture model of primary bronchial epithelial cells cultured at the air-liquid interface (ALI-PBEC) and polarized primary monocyte-derived macrophages. Using this coculture, we studied the contribution of macrophages to epithelial innate immunity, wound healing capacity, and epithelial exposure to whole cigarette smoke (WCS). Coculture of ALI-PBEC with lipopolysaccharide (LPS)-activated M(GM-CSF) macrophages increased the expression ofDEFB4A,CXCL8, andIL6at 24 h in the ALI-PBEC, whereas LPS-activated M(M-CSF) macrophages only increased epithelialIL6expression. Furthermore, wound repair was accelerated by coculture with both activated M(GM-CSF) and M(M-CSF) macrophages, also following WCS exposure. Coculture of ALI-PBEC and M(GM-CSF) macrophages resulted in increasedCAMPexpression in M(GM-CSF) macrophages, which was absent in M(M-CSF) macrophages.CAMPencodes LL-37, an antimicrobial peptide with immune-modulating and repair-enhancing activities. In conclusion, dynamic crosstalk between ALI-PBEC and macrophages enhances epithelial innate immunity and wound repair, even upon concomitant cigarette smoke exposure. Show less
Airway epithelium is an important site for local vitamin D (VD) metabolism; this can be negatively affected by inflammatory mediators. VD is an important regulator of respiratory host defense, for... Show moreAirway epithelium is an important site for local vitamin D (VD) metabolism; this can be negatively affected by inflammatory mediators. VD is an important regulator of respiratory host defense, for example, by increasing the expression of hCAP18/LL-37. TGF-beta 1 is increased in chronic obstructive pulmonary disease (COPD), and known to decrease the expression of constitutive host defense mediators such as secretory leukocyte protease inhibitor (SLPI) and polymeric immunoglobulin receptor (pIgR). VD has been shown to affect TGF-beta 1-signaling by inhibiting TGF-beta 1-induced epithelial-to-mesenchymal transition. However, interactions between VD and TGF-beta 1, relevant for the understanding host defense in COPD, are incompletely understood. Therefore, the aim of the present study was to investigate the combined effects of VD and TGF-beta 1 on airway epithelial cell host defense mechanisms. Exposure to TGF-beta 1 reduced both baseline and VD-induced expression of hCAP18/LL-37, partly by increasing the expression of the VD-degrading enzyme CYP24A1. TGF-beta 1 alone decreased the number of secretory club and goblet cells and reduced the expression of constitutive host defense mediators SLPI, s/lPLUNC and pIgR, effects that were not modulated by VD. These results suggest that TGF-beta 1 may decrease the respiratory host defense both directly by reducing the expression of host defense mediators, and indirectly by affecting VD-mediated effects such as expression of hCAP18/LL-37. Show less
Koppen, B.C.; Mulder, P.P.G.; Boer, L. de; Riool, M.; Drijfhout, J.W.; Zaat, S.A.J. 2019
Cationic host defence peptides (CHDPs), also known as antimicrobial peptides, exhibit a wide range of activities contributing to immune responses and resolution of infections. CHDPs are expressed... Show moreCationic host defence peptides (CHDPs), also known as antimicrobial peptides, exhibit a wide range of activities contributing to immune responses and resolution of infections. CHDPs are expressed across diverse species, are generally amphipathic with less than 50 amino acids in length, and differ significantly in sequence and structure. This chapter focuses on the role of these peptides in immunity. CHDPs are known to function in both innate and adaptive immune responses. These peptides exert both pro-and anti-inflammatory properties, which are likely context dependent based on cell and tissue type, concentration of the peptides, and its interaction with other factors in the microenvironment. Furthermore, the crosstalk between CHDPs and the microbiome and how this may influence mucosal immunity is a rapidly emerging field of research. Overall, the immunomodulatory functions of CHDPs play an important role in the control of infections, regulation of inflammation, and maintaining immune homeostasis. It is thus not surprising that dysregulation of expression of CHDPs is implicated in the susceptibility, pathology, and progression of various diseases. In this chapter, we summarize the immunomodulatory functions of CHDPs, its clinical relevance, and the translational opportunities that these peptides provide for the development of new therapies. Show less
Due to their abilities to eliminate pathogens and modulate host__s immune responses, antimicrobial peptides are considered as potential alternatives for the treatment of infections with (multi-drug... Show moreDue to their abilities to eliminate pathogens and modulate host__s immune responses, antimicrobial peptides are considered as potential alternatives for the treatment of infections with (multi-drug resistant) pathogens. In this thesis the immunomodulatory actions of two peptides have been investigated in order to gain insight in their mechanism of antimicrobial action; human lactoferrin-derived antimicrobial peptide hLF1-11 and the human cathelicidin LL-37. As hLF1-11 is active against infections in animals within a short period, we hypothesized immunomodulatory effects of hLF1-11 on innate immune cells. Results described in this thesis show that hLF1-11 enhances the inflammatory response of monocytes and modulates monocyte-macrophage differentiation resulting in macrophages that display enhanced antimicrobial effector functions. In addition, hLF1-11 drives monocyte-dendritic cell differentiation toward DCs that promote antifungal responses and induce Th17 polarization. Myeloperoxidase was identified as the intracellular target of hLF1-11 mediating immunomodulatory effects of this peptide. We also found that LL-37 was able to modulate monocyte-macrophage differentiation, however different than hLF1-11 as this resulted in macrophages with a pro-inflammatory phenotype. Together, these data underscore the bright future of antimicrobial peptides with immune modulating activity as these peptides might be developed further into a novel class of anti-infectives to which microbial drug-resistance is unlikely to develop quickly. Show less
