Progranulin modulates inflammatory responses to immune challenges by suppressing circulating cytokine levels

Progranulin (PGRN) is a multifunctional growth factor that is widely expressed throughout the body. It has recently been reported that PGRN haploinsufficiency is a major factor causing frontotemporal lobar dementia. Subsequently, many studies, including ours, have demonstrated the neuroprotective and neurotrophic functions of PGRN. We have also shown that PGRN is involved in voluntary exercise-induced neurogenesis and the suppression of neuroinflammation after traumatic brain injury. Because PGRN is expressed in immune cells in peripheral and central tissues, the main purpose of the present study was to elucidate the role of PGRN in inflammatory responses to immune challenges. Male C57BL/6J wild-type (WT) mice or PGRN-deficient (KO) mice of the same background were used in all experiments. We intraperitoneally injected lipopolysaccharide (LPS, 120 μg/kg) into the animals and measured their body temperature for 9 h during the day and their food intake for 24 h. Although LPS induced a fever response and anorexia in mice of both genotypes, the symptoms were much more severe in the KO mice. LPS is known to induce the secretion of inflammatory cytokines, which transmit immune signals from peripheral to central tissues. Thus, we subsequently determined the serum concentrations of the inflammatory cytokines IL-1β, IL-6, and TNF-α at 0, 1, and 3 h after LPS injection. KO mice showed a significantly stronger induction of IL-6 at 3 h and TNF-α at both 1 and 3 h after injection. IL-1β also tended to have stronger induction at 3 h in KO mice, although the difference was not statistically significant. In WT mice, LPS injection increased PGRN mRNA expression but did not enhance serum PGRN concentration. These results suggest that PGRN suppresses excessive inflammatory responses by moderating the secretion of inflammatory cytokines by functioning inside immune cells.