Neuropeptide Y Is Expressed by Rat Mononuclear Blood Leukocytes and Strongly Down-Regulated during Inflammation

Abstract

Neuropeptide Y (NPY), a classical sympathetic comediator, regulates immunological functions including T cell activation and migration of blood leukocytes. A NPY-mediated neuroimmune cross-talk is well conceivable in sympathetically innervated tissues. In denervated, e.g., transplanted organs, however, leukocyte function is not fundamentally disturbed. Thus, we hypothesized that NPY is expressed by blood leukocytes themselves and regulated during inflammation. NPY mRNA and peptide expression were analyzed in mononuclear leukocytes isolated from the blood vessels of healthy rat kidneys, as well as from the blood vessels of isogeneic and allogeneic renal grafts transplanted in the Dark Agouti to Lewis or in the Fischer 344 to Lewis rat strain combination. Depending on the donor strain, acute allograft rejection is either fatal or reversible but both experimental models are characterized by massive accumulation of intravascular leukocytes. Leukocytes, predominantly monocytes, isolated from the blood vessels of untreated kidneys and isografts expressed high amounts of NPY mRNA and peptide, similar to expression levels in sympathetic ganglia. During acute allograft rejection, leukocytic NPY expression drastically dropped to ∼1% of control levels in both rat strain combinations. In conclusion, NPY is an abundantly produced and tightly regulated cytokine of mononuclear blood leukocytes.

Leukocyte accumulation in graft blood vessels during self-limiting acute rejection of rat kidneys

“…As intravascular leukocytes were most numerous at day 9, this time point was further investigated. The cellular composition of intravascular graft leukocytes from day 9 isografts, allografts and untreated control kidneys was published before Holler et al, 2008).…”

“…Spontaneous acceptance of renal allografts transplanted in the Fischer 344 (F344) to Lewis (LEW) or in the F1 (F344 × LEW) to LEW rat strain combinations have been described more than four decades ago (White and Hildemann, 1968;Mahabir et al, 1969). These allografts pass through a severe AR episode and develop chronic allograft nephropathy (CAN) in the long run (White and Hildemann, 1968;Mahabir et al, 1969;Beckmann et al, 2003;Andriambeloson et al, 2004;Bedke et al, 2007;Holler et al, 2008). Strong experimental evidence suggests that chronic allograft rejection, which typically involves intimal and medial remodelling of graft arteries, is irreversibly triggered by AR (Tullius et al, 1998;Joosten et al, 2003;Chapman, 2005;Serón et al, 2005;Nankivell and Chapman, 2006).…”

“…We recently started to investigate self-limiting AR after kidney transplantation in the F344 to LEW rat strain combination. Strikingly, 150 million blood leukocytes accumulate in the vasculature of allografts until day 9 post-transplantation (Holler et al, 2008). In comparison, about the same number of cells are present in the entire extrapulmonary circulation of healthy LEW rats .…”

“…In comparison, about the same number of cells are present in the entire extrapulmonary circulation of healthy LEW rats . Monocytes (∼70%) and T cells (∼19%) represented the most numerous intravascular cells of F344 to LEW allografts, other leukocytes accounted for less than 5% (Holler et al, 2008). The properties of these graft blood leukocytes, however, have not been investigated before.…”

Neuronal Regulation of Mucosal Immune Responses

“…NPY is a typical example of the link between the sympathetic nervous system and the immune system, as NPY releasing sympathetic nerves innervate lymphoid organs, and several immune cell types express NPY or its Y1R (Wheway et al, 2005;Bedoui et al, 2003). In the rat, mononuclear leukocytes were shown to express NPY transcript and protein at high levels (comparable to those found in ganglia), and interestingly, its expression is tightly downregulated after immune cell activation (Holler et al, 2008).…”