Inflammatory macrophages are abundant in kidney disease, stimulating repair, or driving chronic inflammation and fibrosis. Damage associated molecules (DAMPs), released from injured cells engage pattern recognition receptors (PRRs) on macrophages, contributing to activation. Understanding mechanisms of macrophage activation during kidney injury may lead to strategies to alleviate chronic disease. We identified Triggering-Receptor-in-Myeloid-cells (TREM)-1, a regulator of TLR signaling, as highly upregulated in kidney inflammatory macrophages and tested the roles of these receptors in macrophage activation and kidney disease. Kidney DAMPs activated macrophages in vitro, independently of TREM-1, but partially dependent on TLR-2/-4, MyD88. In two models of progressive interstitial kidney disease, TREM-1 blockade had no impact on disease or macrophage activation in vivo, but TLR-2/-4, or MyD88 deficiency was anti-inflammatory and anti-fibrotic. When MyD88 was mutated only in the myeloid lineage, however, there was no bearing on macrophage activation or disease progression. Instead, TLR-2/-4 or MyD88 deficiency reduced activation of mesenchyme lineage cells resulting in reduced inflammation and fibrosis, indicating that these pathways play dominant roles in activation of myofibroblasts but not macrophages. To conclude, TREM-1, TLR2/4 and MyD88 signaling pathways are redundant in myeloid cell activation in kidney injury, but the latter appear to regulate activation of mesenchymal cells.