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Role of C3a and C5a in eosinophil function during allergic asthma

One of the hallmarks of allergic asthma is the development of a Th2 maladaptive immune response. Th2 effector cells are essential for allergic asthma development through their secretion of the interleukins (IL)-5, IL-4 and IL-13, which, in particular, control the expansion and recruitment of eosinophils. While the function of eosinophils during the effector phase of the disease is well appreciated, their roles during allergen sensitization is less-defined. Using floxed C3aR (Quell et al. J. Immunol. 2017), C5aR1 (Karsten et al. J. Immunol. 2015) and C5aR2 (Karsten et al. J. Immunol. 2017) (GFP or tdTomato) reporter mice, we found that pulmonary eosinophils express all three AT receptors. Further, we observed that upon allergic asthma conditions, C5aR1 is upregulated in eosinophils, suggesting that this AT receptor plays important roles in eosinophil function. Interestingly, we not only found surface but intracellular C3aR and C5aR1 expression, suggesting that these AT receptors might be activated by non-canonical production and activation of C3 and C5, similar to what has been demonstrated in T cells (Liszwesky et al. Immunity 2013; Arbore et al. Science 2016).

The main goal of this research is to delineate the expression profile of AT receptors in eosinophils upon allergic asthma inflammation, to study AT receptor functions in eosinophils using eosinophil-specific conditional AT receptor knockout mice, and to assess non-canonical production and activation of C3 and C5 in eosinophils during experimental allergic asthma.


Figure 1 Eosinophils express all AT receptors.Flow cytometry data show that eosinophils at steady state and upon allergic asthma express C3aR, C5aR1 and C5aR2. Further, C3aR is located exclusively intracellularly but not at the cell surface.


References

  1. Karsten CM, Wiese AV, Mey F, Figge J, Woodruff TM, Reuter T, Scurtu O, Kordowski A, Almeida LN, Briukhovetska D, Quell KM, Sun J, Ender F, Schmudde I, Vollbrandt T, Laumonnier Y, Köhl J. Monitoring C5aR2 Expression Using a Floxed tdTomato-C5aR2 Knock-In Mouse. J Immunol. 2017 199:3234-3248.
  2. Quell KM, Karsten CM, Kordowski A, Almeida LN, Briukhovetska D, Wiese AV, Sun J, Ender F, Antoniou K, Schröder T, Schmudde I, Berger JL, König P, Vollbrandt T, Laumonnier Y*, Köhl J*. Monitoring C3aR Expression Using a Floxed tdTomato-C3aR Reporter Knock-in Mouse. J Immunol.2017 199:688-706.
  3. Ender F, Wiese AW, Schmudde I, Sun J, Vollbrandt T,König P, Laumonnier Y*, Köhl J*Differential Regulation of C5a Receptor 1 in Innate Immune Cells during the Allergic Asthma Effector Phase. 2017 PlosONE12(2):e0172446.
  4. Karsten CM*, Laumonnier Y*, Eurich B, Ender F, Bröker K, Roy S, Czabanska A, Vollbrandt T, Figge J, Köhl J. Monitoring and cell-specific deletion of C5aR1 using a novel floxed GFP-C5aR1 reporter knock-in mouse.2015 J Immunol.194:1841-55.